Ingredients extraction by physicochemical methods in food 9780128115213, 0128115211

Table of contents :
Content: Methods for extractions of value-added nutraceuticals from lignocellulosic wastes and their health application / Siddharth Vats --
Modern extraction techniques for drugs and medicinal agents / Sudipta Saha, Ashok K. Singh, Amit K. Keshari, Vinit Raj, Amit rai, Siddhartha Maity --
Advances in extraction, fractionation, and purification of low-molecular mass compounds from food and biological samples / Elzbieta Włodarczyk, Paweł K. Zarzycki --
Valorization of agrifood by-products by extracting valuable bioactive compounds using green processes / Ramiro A. Carciochi, Leandro G. D'Alessandro, Peggy Vauchel, Maria M. Rodriguez, Susana M. Nolasco, Krasimir Dimitrov --
Extraction of bioactive phenolic compounds by alternative technologies / Jorge E. Wong-Paz, Diana B. Muniz-Marquez, Pedro Aguilar-Zarate, Juan A. Ascacio-Valdes, Karina Cruz, Carlos Reyes-Luna, Raul Rodriguez, Cristobal N. Aguilar --
The extraction of heavy metals from vegetable samples / Amra Odobasic, Indira Sestan, Amra Bratovcic --
Extraction and use of functional plant ingredients for the development of functional foods / Rudi Radrigan, Pedro Aqueveque, Margarita Ocampo --
Extracting bioactive compounds from natural sources using green high-energy approaches : trends and opportunities in lab-and large-scale applications / Thalia Tsiaka, Vassilia J. Sinanoglou, Panagiotis Zoumpoulakis --
Assessment of the state-of the-art developments in the extraction of antioxidants from marine algal species / Mayyada El-Sayed, Daisy Fleita, Dalia Rifaat, Hanaa Essa --
The use of ultrasound as an enhancement aid to food extraction / Larysa Paniwny, Alma Alarcon-Rojo, Jose C. Rodriguez-Figueroa, Mihai Toma. Extraction of bioactive compound from olive leaves using emerging technologies / Rui M.S. Cruz, Romilson Brito, Petros Smirnoiotis, Zoe Nikolaidou, Margarida C. Vieira --
Separation of bioactive whey proteins and peptides / Mohamed H. Abd El-Salam, Safinaz El-Shibiny --
Phytochemicals : an insight to modern extraction technologies and their applications / Priyanka Rao, Virendra Rathod --
Extraction technologies and solvents of phytocompounds from plant materials : physicochemical characterization and identification of ingredients and bioactive compounds from plant extract using various instrumentations / Ida I. Muhamad, Nor D. Hassan, Siti N.H. Mamat, Norazlina M. Nawi, Wahida A. Rashid, Nuraimi A. Tan --
An energy-based approach to scale up microwave-assisted extraction of plant bioactives / Chung-Hung, Chan, Rozita Yusoff, Gef Cheng Ngoh.

Citation preview

Ingredients Extraction by Physicochemical Methods in Food Handbook of Food Bioengineering, Volume 4



Edited by

Alexandru Mihai Grumezescu Alina Maria Holban

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2017 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-811521-3 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre Gerhard Wolff Acquisition Editor: Nina Bandeira Editorial Project Manager: Jaclyn Truesdell Production Project Manager: Caroline Johnson Designer: Matthew Limbert Typeset by Thomson Digital

List of Contributors Cristóbal N. Aguilar  Autonomous University of Coahuila, Saltillo, Coahuila, Mexico Pedro Aguilar-Zárate  Instituto Tecnológico de Ciudad Valles, Tecnológico Nacional de México, Ciudad Valles, San Luis Potosí, México Alma Alarcon-Rojo  Autonomous University of Chihuahua, Chihuahua, Mexico Pedro Aqueveque  Development of Agro industries Technology Center, University of Concepción, Chillán, Chile Juan A. Ascacio-Valdés  Autonomous University of Coahuila, Saltillo, Coahuila, Mexico Amra Bratovcic  University of Tuzla, Tuzla, Bosnia and Herzegovina Romilson Brito  MeditBio and University of Algarve, Faro, Portugal Ramiro A. Carciochi  National University of Central Buenos Aires, Olavarría, Buenos Aires, Argentina Chung-Hung Chan  Malaysian Palm Oil Board, Kajang, Selangor, Malaysia Karina Cruz  Autonomous University of Coahuila, Saltillo, Coahuila, Mexico Rui M.S. Cruz  MeditBio and University of Algarve, Faro, Portugal Leandro G. D’Alessandro  Lille University, INRA, ISA, Artois University, University of Littoral Opal Coast, Charles Viollette Institute, Lille, France Krasimir Dimitrov  Lille University, INRA, ISA, Artois University, University of Littoral Opal Coast, Charles Viollette Institute, Lille, France Mohamed H. Abd El-Salam  National Research Centre, Cairo, Egypt Mayyada El-Sayed  American University in Cairo, New Cairo; National Research Centre, Giza, Egypt Safinaz El-Shibiny  National Research Centre, Cairo, Egypt Hanaa Essa  American University in Cairo, New Cairo; Agriculture Research Centre, Giza, Egypt Daisy Fleita  American University in Cairo, New Cairo, Egypt Nor D. Hassan  University of Technology Malaysia, Johor Bahru, Johor, Malaysia Amit K. Keshari  Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India Siddhartha Maity  Jadavpur University, Kolkata, West Bengal, India Siti N.H. Mamat  University of Technology Malaysia, Johor Bahru, Johor, Malaysia Diana B. Muñiz-Márquez  Instituto Tecnológico de Ciudad Valles, Tecnológico Nacional de México, Ciudad Valles, San Luis Potosí, México Ida I. Muhamad  University of Technology Malaysia, Johor Bahru, Johor, Malaysia Norazlina M. Nawi  University of Technology Malaysia, Johor Bahru, Johor, Malaysia Gek Cheng Ngoh  University of Malaya, Kuala Lumpur, Malaysia

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List of Contributors Zoe Nikolaidou  Alexander Technological Educational Institute of Thessaloniki (ATEITh), Thessaloniki, Greece Susana M. Nolasco  National University of Central Buenos Aires, Olavarría, Buenos Aires, Argentina Margarita Ocampo  Development of Agro industries Technology Center, University of Concepción, Chillán, Chile Amra Odobasic  University of Tuzla, Tuzla, Bosnia and Herzegovina Larysa Paniwnyk  Coventry University, Coventry, United Kingdom Rudi Radrigán  Development of Agro industries Technology Center, University of Concepción, Chillán, Chile Amit Rai  Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India Vinit Raj  Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India Priyanka Rao  Institute of Chemical Technology, Mumbai, Maharashtra, India Wahida A. Rashid  University of Technology Malaysia, Johor Bahru, Johor, Malaysia Virendra Rathod  Institute of Chemical Technology, Mumbai, Maharashtra, India Carlos Reyes-Luna  Instituto Tecnológico de Ciudad Valles, Tecnológico Nacional de México, Ciudad Valles, San Luis Potosí, México Dalia Rifaat  American University in Cairo, New Cairo, Egypt Raúl Rodríguez  Autonomous University of Coahuila, Saltillo, Coahuila, Mexico María M. Rodriguez  National University of Central Buenos Aires, Olavarría, Buenos Aires, Argentina José C. Rodriguez-Figueroa  Autonomous University of Chihuahua, Chihuahua, Mexico Sudipta Saha  Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India Indira Sestan  University of Tuzla, Tuzla, Bosnia and Herzegovina Vassilia J. Sinanoglou  Technological Education Institution of Athens, Egaleo, Greece Ashok K. Singh  Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India Petros Smirniotis  Alexander Technological Educational Institute of Thessaloniki (ATEITh), Thessaloniki, Greece Nuraimi A. Tan  University of Technology Malaysia, Johor Bahru, Johor, Malaysia Mihai Toma  Costin D. Neniţescu–Institute of Organic Chemistry of the Romanian Academy, Bucharest, Romania Thalia Tsiaka  Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens; Technological Education Institution of Athens, Egaleo; University of Athens, Athens, Greece Siddharth Vats  Shri Ram Swaroop Memorial University, Lucknow, Uttar Pradesh, India Peggy Vauchel  Lille University, INRA, ISA, Artois University, University of Littoral Opal Coast, Charles Viollette Institute, Lille, France Margarida C. Vieira  MeditBio and University of Algarve, Faro, Portugal Elżbieta Włodarczyk  Koszalin University of Technology, Koszalin, Poland Jorge E. Wong-Paz  Instituto Tecnológico de Ciudad Valles, Tecnológico Nacional de México, Ciudad Valles, San Luis Potosí, México Rozita Yusoff  University of Malaya, Kuala Lumpur, Malaysia Paweł K. Zarzycki  Koszalin University of Technology, Koszalin, Poland Panagiotis Zoumpoulakis  Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation; National Hellenic Research Foundation; University of Athens, Athens, Greece

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Foreword In the last 50 years an increasing number of modified and alternative foods have been developed using various tools of science, engineering, and biotechnology. The result is that today most of the available commercial food is somehow modified and improved, and made to look better, taste different, and be commercially attractive. These food products have entered in the domestic first and then the international markets, currently representing a great industry in most countries. Sometimes these products are considered as life-supporting alternatives, neither good nor bad, and sometimes they are just seen as luxury foods. In the context of a permanently growing population, changing climate, and strong anthropological influence, food resources became limited in large parts of the Earth. Obtaining a better and more resistant crop quickly and with improved nutritional value would represent the Holy Grail for the food industry. However, such a crop could pose negative effects on the environment and consumer health, as most of the current approaches involve the use of powerful and broadspectrum pesticides, genetic engineered plants and animals, or bioelements with unknown and difficult-to-predict effects. Numerous questions have emerged with the introduction of engineered foods, many of them pertaining to their safe use for human consumption and ecosystems, long-term expectations, benefits, challenges associated with their use, and most important, their economic impact. The progress made in the food industry by the development of applicative engineering and biotechnologies is impressive and many of the advances are oriented to solve the world food crisis in a constantly increasing population: from genetic engineering to improved preservatives and advanced materials for innovative food quality control and packaging. In the present era, innovative technologies and state-of-the-art research progress has allowed the development of a new and rapidly changing food industry, able to bottom-up all known and accepted facts in the traditional food management. The huge amount of available information, many times is difficult to validate, and the variety of approaches, which could seem overwhelming and lead to misunderstandings, is yet a valuable resource of manipulation for the population as a whole. The series entitled Handbook of Food Bioengineering brings together a comprehensive collection of volumes to reveal the most current progress and perspectives in the field of food engineering. The editors have selected the most interesting and intriguing topics, and have dissected them in 20 thematic volumes, allowing readers to find the description of basic xv

Foreword processes and also the up-to-date innovations in the field. Although the series is mainly dedicated to the engineering, research, and biotechnological sectors, a wide audience could benefit from this impressive and updated information on the food industry. This is because of the overall style of the book, outstanding authors of the chapters, numerous illustrations, images, and well-structured chapters, which are easy to understand. Nonetheless, the most novel approaches and technologies could be of a great relevance for researchers and engineers working in the field of bioengineering. Current approaches, regulations, safety issues, and the perspective of innovative applications are highlighted and thoroughly dissected in this series. This work comes as a useful tool to understand where we are and where we are heading to in the food industry, while being amazed by the great variety of approaches and innovations, which constantly changes the idea of the “food of the future.” Anton Ficai, PhD (Eng) Department Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, Politehnica University of Bucharest, Bucharest, Romania

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Series Preface The food sector represents one of the most important industries in terms of extent, investment, and diversity. In a permanently changing society, dietary needs and preferences are widely variable. Along with offering a great technological support for innovative and appreciated products, the current food industry should also cover the basic needs of an ever-increasing population. In this context, engineering, research, and technology have been combined to offer sustainable solutions in the food industry for a healthy and satisfied population. Massive progress is constantly being made in this dynamic field, but most of the recent information remains poorly revealed to the large population. This series emerged out of our need, and that of many others, to bring together the most relevant and innovative available approaches in the amazing field of food bioengineering. In this work we present relevant aspects in a pertinent and easy-to-understand sequence, beginning with the basic aspects of food production and concluding with the most novel technologies and approaches for processing, preservation, and packaging. Hot topics, such as genetically modified foods, food additives, and foodborne diseases, are thoroughly dissected in dedicated volumes, which reveal the newest trends, current products, and applicable regulations. While health and well-being are key drivers for the food industry, market forces strive for innovation throughout the complete food chain, including raw material/ingredient sourcing, food processing, quality control of finished products, and packaging. Scientists and industry stakeholders have already identified potential uses of new and highly investigated concepts, such as nanotechnology, in virtually every segment of the food industry, from agriculture (i.e., pesticide production and processing, fertilizer or vaccine delivery, animal and plant pathogen detection, and targeted genetic engineering) to food production and processing (i.e., encapsulation of flavor or odor enhancers, food textural or quality improvement, and new gelation- or viscosity-enhancing agents), food packaging (i.e., pathogen, physicochemical, and mechanical agents sensors; anticounterfeiting devices; UV protection; and the design of stronger, more impermeable polymer films), and nutrient supplements (i.e., nutraceuticals, higher stability and bioavailability of food bioactives, etc.). xvii

Series Preface The series entitled Handbook of Food Bioengineering comprises 20 thematic volumes; each volume presenting focused information on a particular topic discussed in 15 chapters each. The volumes and approached topics of this multivolume series are: Volume 1: Food Biosynthesis Volume 2: Food Bioconversion Volume 3: Soft Chemistry and Food Fermentation Volume 4: Ingredient Extraction by Physicochemical Methods in Food Volume 5: Microbial Production of Food Ingredients and Additives Volume 6: Genetically Engineered Foods Volume 7: Natural and Artificial Flavoring Agents and Food Dyes Volume 8: Therapeutic Foods Volume 9: Food Packaging and Preservation Volume 10: Microbial Contamination and Food Degradation Volume 11: Diet, Microbiome, and Health Volume 12: Impacts of Nanoscience on the Food Industry Volume 13: Food Quality: Balancing Health and Disease Volume 14: Advances in Biotechnology in the Food Industry Volume 15: Foodborne Diseases Volume 16: Food Control and Biosecurity Volume 17: Alternative and Replacement Foods Volume 18: Food Processing for Increased Quality and Consumption Volume 19: Role of Material Science in Food Bioengineering Volume 20: Biopolymers for Food Design The series begins with a volume on Food Biosynthesis, which reveals the concept of food production through biological processes and also the main bioelements that could be involved in food processing. The second volume, Food Bioconversion, highlights aspects related to food modification in a biological manner. A key aspect of this volume is represented by waste bioconversion as a supportive approach in the current waste crisis and massive pollution of the planet Earth. In the third volume, Soft Chemistry and Food Fermentation, we aim xviii

Series Preface to discuss several aspects regarding not only to the varieties and impacts of fermentative processes, but also the range of chemical processes that mimic some biological processes in the context of the current and future biofood industry. Volume 4, Ingredient Extraction by Physicochemical Methods in Food, brings the readers into the world of ingredients and the methods that can be applied for their extraction and purification. Both traditional and most of the modern techniques can be found in dedicated chapters of this volume. On the other hand, in volume 5, Microbial Production of Food Ingredients and Additives, biological methods of ingredient production, emphasizing microbial processes, are revealed and discussed. In volume 6, Genetically Engineered Foods, the delicate subject of genetically engineered plants and animals to develop modified foods is thoroughly dissected. Further, in volume 7, Natural and Artificial Flavoring Agents and Food Dyes, another hot topic in food industry—— flavoring and dyes—is scientifically commented and valuable examples of natural and artificial compounds are generously offered. Volume 8, Therapeutic Foods, reveals the most utilized and investigated foods with therapeutic values. Moreover, basic and future approaches for traditional and alternative medicine, utilizing medicinal foods, are presented here. In volume 9, Food Packaging and Preservation, the most recent, innovative, and interesting technologies and advances in food packaging, novel preservatives, and preservation methods are presented. On the other hand, important aspects in the field of Microbial Contamination and Food Degradation are presented in volume 10. Highly debated topics in modern society: Diet, Microbiome, and Health are significantly discussed in volume 11. Volume 12 highlights the Impacts of Nanoscience on the Food Industry, presenting the most recent advances in the field of applicative nanotechnology with great impacts on the food industry. Additionally, volume 13 entitled Food Quality: Balancing Health and Disease reveals the current knowledge and concerns regarding the influence of food quality on the overall health of population and potential food-related diseases. In volume 14, Advances in Biotechnology in the Food Industry, up-to-date information regarding the progress of biotechnology in the construction of the future food industry is revealed. Improved technologies, new concepts, and perspectives are highlighted in this work. The topic of Foodborne Diseases is also well documented within this series in volume 15. Moreover, Food Control and Biosecurity aspects, as well as current regulations and food safety concerns are discussed in the volume 16. In volume 17, Alternative and Replacement Foods, another broad-interest concept is reviewed. The use and research of traditional food alternatives currently gain increasing terrain and this quick emerging trend has a significant impact on the food industry. Another related hot topic, Food Processing for Increased Quality and Consumption, is considered in volume 18. The final two volumes rely on the massive progress made in material science and the great applicative impacts of this progress on the food industry. Volume 19, Role of Material Science in Food Bioengineering, offers a perspective and a scientific introduction in the science of engineered materials, with important applications in food research and technology. Finally, in the volume 20, Biopolymers for Food Design, we discuss the advantages and challenges related to the development of improved and smart biopolymers for the food industry. xix

Series Preface All 20 volumes of this comprehensive collection were carefully composed not only to offer basic knowledge for facilitating understanding of nonspecialist readers, but also to offer valuable information regarding the newest trends and advances in food engineering, which is useful for researchers and specialized readers. Each volume could be treated individually as a useful source of knowledge for a particular topic in the extensive field of food engineering or as a dedicated and explicit part of the whole series. This series is primarily dedicated to scientists, academicians, engineers, industrial representatives, innovative technology representatives, medical doctors, and also to any nonspecialist reader willing to learn about the recent innovations and future perspectives in the dynamic field of food bioengineering. Alexandru M. Grumezescu Politehnica University of Bucharest, Bucharest, Romania Alina M. Holban University of Bucharest, Bucharest, Romania

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Preface for Volume 4: Ingredients Extraction by Physicochemical Methods in Food Numerous food-related compounds have proved their additional beneficial effects, along with their nutritional properties. Some food ingredients have been utilized for centuries in traditional and preventive therapy for their health-promoting effect, while others may have an impact on various industries (i.e., food, chemical, biotechnological, and pharmaceutical) and even on our environment. A key factor in the production of such ingredients is represented by their physicochemical extraction technique. Extraction methods are variable, and great progress has been made in this field in the past decade. This book describes the most utilized methods developed for ingredients extraction and the anticipated design of future approaches. Intelligent systems have recently emerged to obtain useful and innovative ingredients from plants, exotic fruits, and spices, their impact on the quality and development of the food industry being impressive. This book has aimed to bring together the most interesting and investigated aspects of ingredients extraction and the most important technologies, to obtain specific and valuable food-related compounds for improved food quality, health promotion, and environmental protection in the context of a sustainable food industry. Classical and newest technologies, along with their applicability spectrum and their main advantages and drawbacks, are presented within this volume. The volume contains 15 chapters prepared by outstanding authors from France, the United Kingdom, India, Poland, Mexico, Bosnia and Herzegovina, Chile, Greece, Egypt, Portugal, and Malaysia. The selected manuscripts are clearly illustrated and contain accessible information for a wide audience, especially food scientists, engineers, biotechnologists, biochemists, and industrial companies, but also any reader interested in learning about the most interesting and recent advances on the field of ingredients extraction and food processing.

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Preface for Volume 4: Ingredients Extraction by Physicochemical Methods in Food Chapter 1, prepared by Vats, is entitled Methods for Extractions of Value-Added Nutraceuticals From Lignocellulosic Wastes and Their Health Application. In this work, the author introduces readers to contributions in the field of food ingredients extraction from various sources, such as medicinally valuable phytochemicals, nutraceuticals functional foods, fruit purees and powders, biochemicals, electrolytes blends, health-promoting agents, nutritive oils, antimicrobial products, bioactive compounds, commercially valuable food flavoring and additives compounds of a biochemical nature, proteins, nutritional supplements, and personal and cosmetic care, as well as drugs and pharmacophores from eukaryotic and prokaryotic cultured cells or from plants, animals, and microbes. The main extraction methods, such as standard physical extraction procedures and solvents-based approaches, are also discussed. Saha and collaborators, in Chapter 2, Modern Extraction Techniques for Drugs and Medicinal Agents, reveal various physicochemical methods of extraction that comprise microwaveassisted extraction, pressurized liquid extraction, supercritical fluid extraction, liquid phase microextraction, solid phase extraction, ultrasound-assisted extraction, cloud-point extraction, enzyme-assisted extraction, membrane-based microextraction, and cooling-assisted microextraction. These are the commonly used and modern techniques in terms of isolation and separation of ingredients from both chemical and biological mixtures. Chapter 3, entitled Advances in Extraction, Fractionation, and Purification of Low-Molecular Mass Compounds From Food and Biological Samples, written by Włodarczyk and Zarzycki, gives an overview concerning current extraction and quantification protocols of bioactive substances, which are recently designed for analytical and technological applications of food processing. Generally, extraction, fractionation, and purification are critical issues for both analytical applications and technological processes involving food and biological samples. The authors discuss methodological approaches depending on the expected outcomes and physicochemical properties of a given product. In Chapter 4, Valorization of Agrifood By-Products by Extracting Valuable Bioactive Compounds Using Green Processes, prepared by Carciochi et al., is presented the current challenge for the food industry, related to the exploitation of various by-products as sources of new commodities using eco-friendly technologies with an optimal cost-benefit relationship. The main green technologies used to recover natural products from agrifood by-products, such as enzyme-assisted extraction, ultrasound-assisted extraction, microwave-assisted extraction, electrically assisted extraction, pressurized liquid extraction, supercritical fluid extraction, and instant controlled pressure drop, are presented here. Wong-Paz and coworkers, in Chapter 5, Extraction of Bioactive Phenolic Compounds by Alternative Technologies, describe the advances in the research done on bioactive phenolic compound (BPC) extraction using alternative extraction technologies. In addition, the important parameters influencing its performance, the basic theory of reactions present, and xxii

Preface for Volume 4: Ingredients Extraction by Physicochemical Methods in Food the direct effect of alternative extraction technologies on BPCs are also included. Advantages and drawbacks of the alternative extraction technologies on BPC extraction with regard to conventional extraction technologies are summarized. Finally, a perspective and general conclusion are presented. Chapter 6, The Extraction of Heavy Metals From Vegetable Samples, prepared by Odobašic´ and collaborators, describes types of extraction approaches in order to determine the origin of metals and the efficiency of their removal. It is considered that metals that are in an adsorption and exchangeable phase are more weakly bonded and more easily bioavailable and because of that have anthropogenic origins. Metals in an inert residual fraction indicate natural origin. Thus, these separation approaches bring essential information on the nature and potential impact of various heavy metals in foods. Radrigán et al., in Chapter 7, Extraction and Use of Functional Plant Ingredients for the Development of Functional Foods, offer an interesting collection of technical extraction particularities of active principles of biomaterials, with emphasis on their importance in the development of functional foods, since some biomaterials are used as supplements in the diet. In Chapter 8, prepared by Tsiaka and coworkers, Extracting Bioactive Compounds From Natural Sources Using Green High-Energy Approaches: Trends and Opportunities in Laband Large-Scale Applications, are explored the main concepts and principles of high-energy extraction techniques in selective and targeted extraction of bioactive or functional molecules with health-promoting properties. In addition, a special allusion is made to the significance of optimization strategies and experimental design models in the improvement of the extraction procedures. Furthermore, arguments presented in this review are supported by a variety of examples and peer-reviewed articles published over the past 3 years. Finally, the possibilities and economic feasibility of adopting and scaling up high-energy extraction techniques to the industrial level is investigated in order to define the framework of their implementation and the future potential. El-Sayed et al., in Chapter 9, entitled Assessment of the State-of-the-Art Developments in the Extraction of Antioxidants From Marine Algal Species, critically assess the state-of-the-art methods for extracting antioxidants, with emphasis on sulfated polysaccharides (SPs), from green, red, and brown algae. The evaluation made by these authors is primarily based on the yields and antioxidant activities of the extracted SPs, in addition to other technical, economic, and environmental criteria. Chapter 10, The Use of Ultrasound as an Enhancement Aid to Food Extraction, written by Paniwnyk and collaborators, covers a range of areas that have employed ultrasound to process food materials, such as extraction of plants, seeds, and fruit; the recycling of food waste; and the effect on the properties of meat and dairy products. Some discussion on scale-up processes is also included. xxiii

Preface for Volume 4: Ingredients Extraction by Physicochemical Methods in Food In Chapter 11, Extraction of Bioactive Compounds From Olive Leaves Using Emerging Technologies, Cruz et al. discuss extraction techniques including microwave, supercritical fluid, superheated liquid, and ultrasound that are used to extract bioactive compounds from olive leaves, as well as their antioxidant and antimicrobial properties. El-Salam and El-Shibiny, in Chapter 12, Separation of Bioactive Whey Proteins and Peptides, highlight the basic principles and application of the technologies used for the isolation of casein macropeptide, lactoferrin, and lactoperoxidase from cheese whey. Also, methods for the separation of bioactive peptides from whey protein hydrolysates are presented. Chapter 13, Phytochemicals: An Insight to Modern Extraction Technologies and Their Applications, prepared by Rao and Rathod, provides a holistic insight into the modern approaches for physicochemical extraction alongside conventional techniques, giving a balanced outline of the applications and latest developments of each technique. Chapter 14, prepared by Muhamad et al., Extraction Technologies and Solvents of Phytocompounds From Plant Materials: Physicochemical Characterization and Identification of Ingredients and Bioactive Compounds From Plant Extract Using Various Instrumentations, aims to review several physicochemical extraction techniques, including conventional and advanced techniques, such as solvent extraction, microwave-assisted extraction, ultrasonicassisted extraction, aqueous extraction, enzymatic extraction, and supercritical fluid extraction. These physicochemical characterizations of ingredients and bioactive compounds using various instrumentations could provide informative and scientific reference for diverse potential uses of plant extracts, especially for nutraceuticals and functional food applications. Chan and collaborators in Chapter 15, An Energy-Based Approach to Scale Up MicrowaveAssisted Extraction of Plant Bioactives, discuss the optimization and modeling techniques based on energy-based parameters that enable scale-up of microwave-assisted extraction (MAE) of plant-derived bioactive compounds. Energy-based parameters, namely absorbed power density (APD) and absorbed energy density (AED), are able to characterize the extraction kinetics of MAE in predicting the extraction profiles and the optimum conditions at various conditions, particularly at larger-scale operations. This chapter also discusses the applications of APD and AED in equipment design, operational flexibility, and adaptability for various types of plant extraction with the aim to commercialize MAE. Alexandru M. Grumezescu Politehnica University of Bucharest, Bucharest, Romania Alina M. Holban University of Bucharest, Bucharest, Romania

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CHAPTE R 1

Methods for Extractions of Value-Added Nutraceuticals From Lignocellulosic Wastes and Their Health Application Siddharth Vats Shri Ram Swaroop Memorial University, Lucknow, Uttar Pradesh, India

1 Introduction Nature is the foremost and oldest inexhaustible source of chemotypes and pharmacophores (Mukherjee and Wahile, 2006). The 21st century has seen a wide and explosive surge in natural product chemistry because of new compounds with diversified structural and chemical properties. With the change in the drug discovery process, there is a need for the improvements in natural product research to maintain the cutting edge of alternative medicines (Mukherjee and Wahile, 2006). According to the International Environment Technology Centre’s (United Nations Energy Program) report, the types and the volume of biomass waste generated have increased because of intensive agricultural practices to meet the needs of growing populations. In most of the agricultural practicing countries, like India and China, the major chunk of lingocellulosic waste generated remain unutilized either are burned to make way for new crops or are allowed to rot, eventually causing harm to the environment by emitting methane and generating CO2, which causes climate change (DTIE, 2009). Obtaining value-added products from plants has gained momentum. But there is complete negligence toward forests wastes; these can also be the source of various valueadded products (Vats et al., 2013). Similarly, a major share of forest waste also contributes to forest fires and other environmental changes. Forests are rich in diverse medicinal plants; the waste generated from them can be explored for extraction of medicinal valuable products, because the situations for the health care sector also have challenges from new emerging diseases. Stressful lifestyles, adulteration in the food, rising antibiotic resistance among microbes, all provide the right platform for the emergence of new global diseases. The area where we see a justifiable great scope for the natural health-care product is in metabolic diseases, immunosuppressants, and diseases caused by antibiotic resistant microbes, DNA damage, cellular injuries, and so on. Cancers and infectious diseases kill millions of people worldwide. Various reactive oxygen species (ROS), oxidize different intracellular Ingredients Extraction by Physicochemical Methods in Food http://dx.doi.org/10.1016/B978-0-12-811521-3.00001-6

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2  Chapter 1 components and lead to cancer, aging, heart failure, diabetes, neurodegenerative diseases, and so on. Alternative drugs are losing their edge against the metabolic diseases and infectious microbes with many being challenged by the resistant microbes. The rise in resistant infectious microbes and disadvantages associated with synthetic anticancerous drugs have put phytochemicals on top of the research list of microbiologists and oncologists. Providing economical anticancerous and antimicrobial drugs with negligible side effects is the only ground-level solution. The packaged food market is growing with an ever-increasing rate. The use of additives and preservatives like sodium benzoate (SB), sodium thiosulfates (ST), sodium nitrates (SN), oxalic acid (OA), sodium citrate (SC), and benzoic acids (BA), used on large scale. But it has been found that all major additives used for any purpose in food are also responsible for various health-related issues. The future for natural product-based drugs is bright as a wide range of terrestrial and marine plants and herbs found in extreme geographic and physical conditions are unexplored. Biomasses generated from trees, plants, and shrubs growing in extreme geographic conditions contain some special components with great medicinal values.

1.1  Medicines and Present Scenario Cheap and better medicines, nutritious food, and chemical-free food preservation strategies are the most important basic necessities for mankind of the present and future centuries (Sun and Cheng, 2002). A diet rich in organic food, fruits, and vegetables may decrease the chances of deadly diseases like heart diseases, cancers (Boyer and Liu, 2004). Vegetables, fruit, and plant materials are rich sources of nonnutritive bioactive chemicals called phytochemicals, like flavonoids, alkaloids, cartenoids, phenolics, and other phytochemicals. “Eating one apple each day keeps doctor away” is also scientifically proven that there is an inhibition of cancer cell proliferation, oxidation of lipids, and lowering of blood cholesterol level by consumption of the same (Boyer and Liu, 2004). Epidemiological studies have also confirmed health benefits associated with phytochemicals. The traditional Indian medicine system Ayurveda utilized phytochemicals obtained from plants and herbs to impart health benefits among humans (Moon et al., 2010). Most of the economically leading nations of the world also lead the number of deaths due to cardiovascular diseases and cancers. More than 25% of total drugs available in the market are made up of plants or plant-derived substances (Ameen et al., 2011). In recent years plant-derived metabolites are analyzed and investigated on a large scale as a source of new drugs by considering the antibiotic resistance among microbes for conventional and presently available antibiotics (Ameen et al., 2011). Plants synthesize secondary metabolites as defensive molecules against predations and microbial attacks (Liu, 2004; Mallikharjuna et al., 2007). Chemoprevention and chemotherapy are two separate terms with completely different meanings. Some important issues that make them more complex are age and cancer types. Chemoprevention can be best for healthy people as it is best to prevent them for getting cancers but should be

Methods for Extractions of Value-Added Nutraceuticals  3 less toxic and free from side effects. Chemotherapy is a potent weapon against patients who already have tumors or cancers (Aggarwal et al., 2004).

1.2  Main Classes of Phytochemicals and Their Sources There are various types of phytochemicals and they belong to many classes. Concentrations and quantities of different phytochemicals vary in different plants (Table 1.1). Table 1.1: Main classes and source of phytochemicals. S. no.

Main Group

Examples

1.

Alkaloids

2.

Anthocyanin

Caffeine, theobromine, Coffee, tea, onion, curly kale, theophylline green bean, broccoli, endive, celery, cranberry, orange juice, salad tomato, bell pepper, strawberry, broad bean, apple, grape, red wine, tomato juices, cabbage, carrot, mushroom, pea, spinach, peach, and white wine Malvidin, cyanidin Flowers, fruits, and vegetables

3.

Carotenoids

4.

Coumestans

5.

Flavonoids

6.

Monoterpens

7.

Phytosterols

8.

Organosulfides

9.

Stylbenes

Beta-carotene, lutein lycopene Coumestrol

Main Sources

Tomatoes, watermelon, guava, and pink grapefruits Split peas, pinto beans, lima beans, alfalfa and clover sprouts, soy products, cereals and breads, nuts and oilseeds, vegetables, alcoholic beverages, fruits, and nonalcoholic beverages Epicatechin, hesperidin, Seeds, citrus fruits, olive oil, tea, isorhamnetin, and red wine kaempferol, myricetin, narinfin, nobiletin, oroanthocyanidins, quercetin, rutin, tangerertin Geraniol, limonene Orange, citrus peel oils, cherry, spearmint, caraway, lemongrass Beta-sitosterol Nuts and seeds, plants oils, fruits, and vegetables Allicin, glutathione, Garlic indole-3-carbinol Pterostilbene, Polygonum cuspidatum resveratrol

References Kern and Lipman (1977); Mukherjee and Menge (2000)

Wang et al. (1997); Bridle and Timberlake (1997); Ribereau (1974) Mortensen (2006) Thompson et al. (2006)

Middleton et al. (2000)

Crowell (1997) Weihrauch and Gardner (1978) Srivastava et al. (1997) Aggarwal et al. (2004); Kundu and Surh (2008); Ulrich et al. (2005) (Continued)

4  Chapter 1 Table 1.1: Main classes and source of phytochemicals. (cont.) S. no. 10.

Main Group Triterpenoids

Examples Ursolic

11.

Xanthophylls

Astaxanthin, betacrytoxanthin

12.

Isoflavones

Diadzein, genistein

13.

Hydroxycinamic Chicoric, coumarin, acids ferulic acid, scopoletin

14.

Lignans

Sylamarin

15.

Monophenols

Hydroxytyrosol

16.

Isothyiocynates, thiocynates

17.

Polyphenols

Curcumin

18.

Others

Capsaicin, ellagic acid, gallic acid, rosmarinic acid, tannic acid

Main Sources Rosa woodsii, Prosopis glandulosa, Phoraderndran juniperinum, Syzygium claviflorum, Hyptis capitata, Ternstromia gymnanthera Yellow corn, microbial xanthophylls, alfalafa, pimiento pepper, dehydrated lettuce meal clover meal

Soybeans and soy foods, leguminous plants, fruits, whole grains, clover, and oilseeds Citrus fruits, Brassica oilseed, corn flour, raspberries, plums, and umbelliferous vegetables Nuts and oilseeds, cereals and breads, legumes, fruits, vegetables, soy products, processed foods, alcoholic and nonalcoholic beverages, and flax seed Fruits and vegetables, seeds, cereals, berries, wine, tea, onion bulbs, aromatic plants, and olive oils Caper, eruca sativa, wild mustard (Brassica napus)

References Kashiwada et al. (1998)

Swallen and Gottfried (1942); Bhosale and Bernstein (2005); Brambila et al. (1963) Kaufman et al. (1997); Kurzer and Xu (1997) Ho (1992)

Thompson et al. (2006)

Goya et al. (2007b); Dimitrios (2006)

Esiyok et al. (2004); Morra and Kirkegaard (2002) Turmeric, black berry, raspberry, Manach et al. plum, cherry, yellow onion, apple, (2004) apricot, tomato, red wine, green tea, beans, soy flour, peach

2  Phytochemicals and Health Since the beginning of human civilization diseases have affected humans and their livestocks. The only medicine they had was the food they ate. Plants and animal-based food was the main source for food and medicines. Today, due to pollution, contamination, and adulteration in food, stressful hectic work routines, busy lifestyles, and heavy dependence on packaged food have led to many diseases. India is one of seven hot spots in terms of biodiversity of flora and fauna. The land has provided habitat rich in medicinal plants and 30% of the

Methods for Extractions of Value-Added Nutraceuticals  5 world’s cattle, out of which 7500 plants species have proven medicinal values (Kirtikar and Basu 1918). Numerous studies have been published on the antimicrobial activities of plant extracts against different types of microbes (Dorman and Deans, 2000; Shan et al., 2007). Stems of Fadogia agrestis showed the presence of saponins, steroids, terpenoids, flavonoids, tannins, anthraquinone, glycosides, and alkaloids. Extracts demonstrated antibacterial activity against Staphylococcus aureus, S. spp., Bacillus subtilis, and Escherichia coli (Ameen et al., 2011; Yakubu et al., 2005). According to the report US Cancer Statistics: 2007 Incidence and Mortality, published by the Centers for Disease Control and Prevention, every year more than half a million Americans lose their lives to cancer and more than this to heart disease (Jemal et al., 2007). Cancer is the second leading cause of death in the United States of America after heart disease. Tables 1.2A and 1.2B show the major types of cancer affecting males and females in the USA. Humans have always searched for drugs to prevent diseases. Like a secular tradition, herbal plants have always been used by every culture and country for primary health care. The ultimate source of drugs is medicinal plants and herbs, which are abundant in nature. But what matters is that part of the plant should be extracted at the right time, the right season, and the right stage of its growth (Shahid-Ud-Daula and Basher, 2009). Pathogens and diseases have affected humans and livestocks since the beginning of time. Humans have always searched and needed drugs to prevent diseases. Like a secular tradition, herbal plants have always been used by every culture and country for primary health care. Antibiotics are losing their edge in the fight against diseases and pathogens. Many antibiotic resistance microbes like quilone and ciprofloxacin resistance Table 1.2A: Major types of cancers among men in America. S. no.

Most Common Cancer Among Men

1. 2.

Prostate cancer Lung cancer

3.

Colorectal cancer

Description 156.9; First among all races and populations + Hispanic males 80.5; Second among white, black, American-Indian, and Asia/Pacific island men 52.7; Second for Hispanic populations and third among white and black, American-Indian, and Asian/Pacific islander men

Table 1.2B: Major types of cancer among women in America. S. no.

Most Common Cancers Among Women

1. 2.

Breast cancer Lung cancer

3.

Colorectal cancer

Description 120.4; This is first among the women of all races + Hispanic population 54.5; Second for white, black, and American-Indian but third for Asian/ Pacific islander + Hispanic women 39.7; Second for Asian/Pacific islander + Hispanic women, third for white, black, and American-Indian women

6  Chapter 1 Pseudomonas aeruginosa (QCPRA), methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant S. aureus (PRSA), vancomycin resistant Enterococcus (VRE), pose a challenge to our well being. Many food-borne pathogens, such as E. coli, Salmonella, and Campylobacter, are responsible for diarrhea and gastroenteritis that have resistance to antibiotics. Sexually transmitted bacteria responsible for gonorrhea, penicillin-resistant Streptococci causative agent for pneumonia, microbes responsible for tuberculosis, influenza, HIV, and malaria all have become antibiotic-resistant (Haydel et al., 2008).

2.1  Package Food and Health Issues Packaged foods have become part of our daily lives and there is a huge dependence on them (Mamur et al., 2012). To add shelf life, preventing food from spoiling and achieving desired color, taste, and texture, chemical additives and preservatives are added to the packaged food (Mamur et al., 2012). Additives and preservatives like SB, ST, SN, OA, SC, and BA, are used on a very large scale in packaged food. It has been confirmed from various studies that these food preservatives have done more harm to human health than serving any good (Gamze et al., 2014). Regular consumption of food additives above the acceptable daily intake (ADI) promote cancers, aging, asthma, ulcerative colitis, kidney stones, urinary problems, hypertension, and disturb normal metabolic reactions. Many metabolic reactions generate ROS and free radicals, neutralized by the body’s efficient selfdefense mechanism to maintain cellular homeostasis (Halliwell and Gutteridge, 2007b). The presence of reactive species in excess causes oxidative damage to cellular biomolecules. DNA, proteins, and polyunsaturated fatty acids (PUFA) present in membranes are the most important biomolecules of any cells. Any damage to them can lead to serious problems and diseases (Rajesh et al., 2013). Cell membranes play an important role in cell adhesions, cell signaling, ion conductivity, and cell potential. Any damage to cell membranes can lead to cell death (Pagán and Mackey, 2000). DNA stores the information that governs all the functions of somatic and germ cell lines. DNA during the division of the cells undergoes replication and this information is then translated into proteins, which are part of all kinds of biochemical and physiochemical reactions occurring intracellular or extracellular. Therefore, any kind of damage to DNA molecules can alter the normal reaction and fundamental process of the both somatic and germ line cells, which are the unit of life (structural and functional). And any kind of biomolecular or organelle damage due to exposure to a number of endogenous and exogenous agents over a period of time affects the normal functioning of the cells. The aim of this study is to analyze the protective effect of phytochemicals. As the body has its own defensive mechanism to neutralize ROS, but with the consumption of packaged food containing chemical additives, oxidative stress can not be lowered by the natural defense system of body (Droge, 2002). Antioxidants must be supplied exogenously. And the phytochemicals obtained from plants can be commercially exploited because of their defensive role in maintaining cellular homeostasis. SB helps

Methods for Extractions of Value-Added Nutraceuticals  7 stop the fermentation or acidification of foods and can be found in sodas and many fruit juices (Saad et al., 2005), and when get mixed with vitamin C, it can create benzene, a known carcinogen (Clauson et al., 2003). Preservatives like SNs and nitrites are used in meats (ham and bacon), and gives hot dogs their red coloring. The American Cancer Society recommends avoiding consumption of processed meats containing nitrites, because it is linked to asthma, nausea, vomiting, headaches, and cancer (Kilfoy et al., 2011). Preservative benzoic acid on the other hand is associated with damage to the nervous system, asthma, and increased hyperactivity in children (Clauson et al., 2003). BA is used in processed foods like cheeses, varied sauces, margarine, fruit juices, carbonated beverages, and meats. ST and sulfites are used to prevent fungal spoilage and browning of peeled fruits and vegetables and are responsible for causing allergic reactions (Vally et al., 2009). SC should be avoided by people suffering with kidney disease, heart disease, high blood pressure, a history of heart attack, urinary problems, swelling (edema), or chronic diarrhea (such as ulcerative colitis, Crohn’s disease) and should avoid the use of SC as it can increase the chances of all these mentioned diseases. OA is responsible for kidney stones in many patients. It is used in industry as a bleaching agent and for rust removal. In the body, OA can combine with calcium in the kidneys to form kidney stones in susceptible people. OA is poisonous when consumed in high quantities, so people with certain health conditions should avoid high oxalate foods.

3  Phytochemicals and Health Benefits 3.1 Alkaloids Alkaloids are plant products that have a great impact on the social, economic, and political matters for a long time. These are major players in the field of therapy and include agents like atropine, morphine, quinine, vincristine (Fazel et al., 2008). Researchers are working on Xylocarpus grantum root bark containing, alkaloid N-methyl-flindersine and many inorganic compounds like Na+, K+, Ca++, Cl–, and Mg++ in leaves. Jordan et al. (1991) found anticancerous effects of vinca alkaloids. They took five vinca alkaloids and studied inhibitory activity against a proliferation of cancer. The antiproliferative activity of vinca alkaloids was based on the observation of the inhibition of cell growth by arresting cells at metaphase even at the lowest effective concentration with almost nil microtubule depolymerization and spindle disorganization instead by altering the dynamics of tubulin at the end of spindle microtubules. Ergot alkaloids are one type of alkaloids that find clinical use for the treatment of complicated problems like uterine atonia, postpartum bleeding, sensile cerebral insufficiency, hypertension, migraine, and so on (Kren, 1997; Mukherjee and Menge, 2000). Ergot alkaloids are produced from fungus Claviceps purpurea. In the field of agriculture pure alkaloid standards are used to investigate the presence of alkaloid and glycoalkaloid in agricultural products like potatoes as these also cause acute toxicity. All those new varieties of potatoes to be commercialized first and have to be ensured to

8  Chapter 1 be free of acute toxicity of alkaloids. Two important sources of alkaloid for standards are glycoalkaloid alpha chaconine and alkaloid solanidine (Bushway et al., 1987). Another important bioactive alkaloid is tetrahydro-beta-carbolines, which are mainly present in the mammalian tissues, fluids, and brain (Herraiz and Galisteo, 2003), but nobody is sure about their biological origin. Some fruits and juices contains 1-methyl-1,2,3,4-tetrahydro-βcarboline-3-carboxylic acid and 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, generally in citrus fruits 1-methyl-1,2,3,4-tetrahydro-β-carboline (mainly found in tomato juice, tomatoes, and kiwi) and 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-β-carboline. All the fruits that contain these alkaloids are good sources of antioxidants and show good free radical scavenger activity. Piper retrofractum fruits are sources of piperidine alkaloids, namely piperoctadecalidine and pipereicosalidine (Wong et al., 1992). Purine alkaloids are one of the main phytochemicals and caffeine, theobromine and theeophyline are the main flag bearers of this category. Caffeine is most abundant in coffee, tea, and yerba; on the other hand, cocoa seeds are the most abundant source of theobromine. Purine alkaloids caffeine and theobromine from the fruits of tea Camellia sinensis L. were studied by Suzuki and Waller (1985). They found that caffein amounts vary with the growth and growing season till the complete ripening of fruits. Taste, color, and flavor of coffee and tea make them good and bad. Suzuki and Waller (1985) also quantified the purine alkaloid content in the fruit. Dry fruit’s pericarp contains the maximum with seed coat, fruit stalk, and the seed in decreasing level respectively.

3.2 Anthocyanins Out of various phytochemicals being colorful anthocyanins are most attractive and widely recognized. These are most abundant in fruits and vegetables (Wang and Stoner, 2008). Anthocyanins are plants pigments that belong to the flavonoid group of phytochemicals. Main sources of anthocyanins are teas, wines, vegetables, nuts, olives, honey, cocoa, and cereals. Commercially, anthocyanins are produced from grapes, elderberry, red cabbage, roselle, and so on (Bridle et al., 1996). The red color of wines, which evolves on aging, is also because of anthocyanins present in the grapes skin (Ribereau, 1974). Anthocyanin absorbs light at 500 nm because of the presence of conjugated bonds in their structures and give purple, blue, and red colors to vegetables and fruits (Wang and Stoner, 2008). Anthocyanins are bioactive phytochemicals with strong antioxidant activity and free radical scavenging activities (Tsuda et al. 1997, 2004a,b). Anthocyanin’s rich mixture of flavonoids provide protection to DNA and reduce estrogen activity, inhibition of enzymes, and improve immunological responses by enhancing the production of cytokines, reducing inflammation and lipid peroxidations, and strengthening the membrane by decreasing the permeability of capillary and their fragility (Lila, 2004). Tsuda et al. (2004b), when mice were fed with a high fat diet with anthocyanins extracted from purple corn, found effective inhibition of the increase of adipose tissue and body weight gain. Lila (2004) found that biological activity

Methods for Extractions of Value-Added Nutraceuticals  9 of anthocyanin pigments present in the human body are either phytochemical dependent or almost never independent. Generally, anthocyanin and other flavonoid components or nonflavonoid components provide full benefit when they work synergistically. Plants that have a rich source of anthocyanin have a complex phytochemical cocktail and these are products, which are produced by the plants as attractive agents and in their defense from pathogens and predators. Anthocyanins are present in flowers, fruits, and vegetables and show very good oxygen radical absorbing capacity. Wang et al. (1997) determined antioxidant activity of 14 anthocyanins and found kuromanin had the highest antioxidant activity among them. Today anthocyanins are a hot topic for research because of health benefits. Anthocyanins act as nutraceuticals because of their antioxidant effects and are used in therapy because of their role in treating cardiovascular diseases, cancers, and even HIV-1 (Lila, 2004; Talavéra et al., 2006; Zafra-Stone et al., 2007). In vitro experiments have proved that anthocyanins are good antioxidant with beneficial effects in humans but the real potential can be achieved when researchers understand their in vivo bioavailability with functions. If researchers look at the industrial point of view, especially the wine industries where grapes and other fruits are used, which are good sources of anthocyanins, they are influenced by the phenomena of copigmentations.

3.3 Cartenoids Color adds value to the food and it is the color of food that gives the first impression about its quality and taste. Color makes food more tempting and helps in fulfilling expectations. There are many reasons that are associated with the addition of color to food, like to compensate color lost during processing of food, support the already existing colors, to tackle colorbased quality variations, and to add color to uncolored food (Mortensen, 2006). Carotenoids are one of the most important pigments and natural colorants. Carotenoids are lipid soluble and are generally yellow, orange, and red pigments found among all higher plants and in few animals (Mortensen, 2006). Carotenoids are classified in two categories; one is made up of only carbon and hydrogen, and other has carbon, oxygen, and hydrogen and are called carotenes and xanthophyls, respectively. European legislation has set guidelines that carotenes can be obtained from plants we eat and there is specifically mention of carrots, oils obtained from plants like from oil palm fruits, alfalfa, and some grasses. The main types of carotenes are alpha carotenes and beta carotene. Lycopenes is another important carotene. Lycopene’s concentration is highest in tomatoes, with 28–42 micrograms per gram, which increases up to 86 – 131 micrograms per gram of weight in juices and sauces (Rao et al., 1998). Lycopene is the precursor for the beta form of carotenes and generally found in the plants containing beta carotenes. Single lycopene molecules can neutralize oxygen molecules and one lycopene molecule can scavange more than one ROS because of the number of conjugated double bonds (Krinsky and Johnson, 2005). This makes lycopene a good candidate for chemopreventive and chemotherapeutic drugs. Lycopene has good antiprostate

10  Chapter 1 cancer activities based on antiproliferative and proapoptotic properties as this isomer gets accumulated within the prostate region (Krinsky and Johnson, 2005). Lutein is another common carotenoid and obtained from Aztec marigold. Annatto tree seeds are the source for the colorant annatto. Use of annatto is more restricted in the European Union than in the United States. Paprika obtained from fruits pod of capsicum annuum is a well-known spice and is used as a colorant more than as a spice. Paprika is the source of various pigments and, most importantly, one is capasnthin and is almost 50% of the total pigments present in the paprika (Minguez-Mosquera and Hornero-Mendez, 1993). Saffron is also an important source of carotenoids and whole stigma is added to the food for taste and color.

3.4 Xanthophylls Xanthophylls are yellow pigments that are one of the important divisions of the carotenoid group. The word xanthophylls is made up of the Greek word xanthos, meaning yellow, and phyllon, meaning leaf. The major difference between xanthophylls and carotenes is that xanthophylls contain oxygen atoms in the form of a hydroxyl group or epoxides while carotenes are molecules with only hydrocarbons and no oxygen. Yellow corn contains various pigments and primarily xanthophylls and some amount of carotenes (Swallen, 1942). Xanthophylls are concentrated at leaves like all other carotenoids and modulate the light energy. Xanthophylls found in all other animals or humans or other dietary animals are only plant derived. The three main types of oxygenated carotenoids in human diets are lutein, zeaxanthin, and cryptoxanthanin and their concentration in the human blood is high. In algae and vascular plants xanthophylls pigments play various important structural, as well as functional roles (Niyogi et al., 1997). Xanthophylls are found in all photosynthetic eukaryotes in bound form generally with chlorophyll molecules and proteins present in the integral membranes.

3.5 Coumestan Coumestan are derivatives of coumarin and forms the central core for a variety of natural compounds. Some of the phytochemicals also have oestrogenic properties and are termed as phytoestrogens and mainly belong to the flavonoids groups (Kuhnau, 1976). These are called phytoestrogen as they have same effect on the central nervous system of human as estrogen. Main sources of coumestans are split peas, pinto beans, lima beans, alfalfa, and clover sprouts. Coumstans are one of the three classes of falvonoids that are termed as phytoestrogens, namely coumestans, prenylated flavonoids, and isoflavones. Coumestans have physical and chemical properties similar to isoflavones (Humfrey, 1998). Phytoestrogens have nonsteroidal structures, which makes them resemble mammalian estrogens. They can bind to estrogen receptors (ER) in both agonists and antagonists for estrogen (Jenkins et al., 2002). According to Thompson et al. (2006), phytoestrogens like coumestan, lignans, and isoflavones may be potential candidates to treat cancers associated with hormones.

Methods for Extractions of Value-Added Nutraceuticals  11

3.6 Flavonoids Vegetables, berries, and fruits and beverages are good sources of flavonoids and are associated with reducing the risks of a number of diseases. Flavonoids have shown positive effects on the immune system both in vitro, as well as in vivo (Middleton and Kandaswami, 1992). Flavonoids are phytochemicals of low molecular weight, have three-ring structures, and are of various types based on the different substitutions (Middleton et al., 2000). Flavonoids have several important roles in plants as antimicrobials, antioxidant, attractors, light receptors, and many other biological activities (Pietta et al., 2000). The main possible mechanism is their antioxidant activity. Antioxidants evolved as an important part of natural defense mechanisms among living organisms (Jovanovic et al., 1994). These are the molecules that scavenge the free radical species and inhibit the chain reactions that can damage vital molecules of living organisms. Though they are very beneficial, one antioxidant molecule interacts with one free radical so they should be replenished to meet the constant challenge posed by various free radicals. Flavonoids have various biological activities. Today, flavonoid-based products are flushing in the market. For example, propolis is the material bees use to protect their hives. This propolis has various biological activities like antibacterial, antiviral, antiinflamatory, and also anesthetic properties. Of more than 150 components present in them, flavonoids are the major player (Chang et al., 2002). Animal and cellular studies confirm that flavonoids inhibit cancer proliferation. These studies are conducted with high concentrations of flavonoids, but will they help in the same way when tested on humans. Would humans be able to cope with the high concentration of flavonoid? These questions have to be answered. Intake of flavonols and flavones can reduce the chances of heart disease, like myocardial infarction and strokes that increase the phytochemical productivity employs the basic understanding of genes regulating and controlling the pathways responsible, and lead to the synthesis of these compounds in fruits and other vegetables. Biochemical and molecular techniques employability enhances the production of phytochemicals.

3.7 Isoflavones Isoflavones are a subclass of flavonoinds and are scarcely distributed in nature. Soybeans are the main source of isoflavones and soy foods are consumed on a high level in Asian countries, mainly Pacific (Russo et al., 2010). Out of various isoflavones, genistein has the maximum percentage among leguminous plants and helps in fighting various kinds of cancers. Breast and prostate cancers among humans are the most common types. Genistein has a strong role as anticancerous biomolecules against breast and prostate cancers (Lampe et al., 2007). Genistein phytochemicals and their analogous molecules resemble estrogen hormones, molecular structure-wise and is the reason they are also called “phytoestrogen.” ERs, like ER alpha and ER beta, receive various estrogens, like hormones, like 17-beta estradiol E2, which by the use of these receptors, act on the estrogen dependent tissues, like the uterus, ovary, and

12  Chapter 1 breast. ER alpha is associated with the growth effects of estrogen and found mainly in the uterus and liver while ER beta have antiproliferative properties and are found mainly in the ovary (Russo et al., 2010). Genistein inhibits growth of most types of hormone dependant and independent cancer cells (Chang et al., 2009).

3.8 Monoterpenes Monoterpenes are phytochemicals of C10 representation of terpenoid family. Gershenzon et al. (1989) studied biosynthesis and catabolism of monoterpenes. Russin et al. (1989) studied the effects of monoterpenoids in inhibition of mammary carcinogenesis in rats. In this study the authors focused on limonene and oxygenated [(−)-menthol] and nonoxygenated (rf-limonene) monocyclic forms, oxygenated (1,8-cineole) and nonoxygenated [(±)-a-pinene) bicyclic forms and oxygenated [(±)-linalool and nonoxygenated 03-myrcene] acyclic forms. Dietary feed of each of the monocyclic terpenes, d-limonene or (−)-menthol resulted in a significant inhibition of mammary carcinogenesis. Out of all of them menthol was more potent even to limonene. Monoterpens are also used as fumigating agents. Lee et al. (2003) found monoterpenoids in fumes form; they show antipest effects and can be used to kill pests and insects for several stored products. Concentrations of 50 µg/mL in air caused 100% mortality in rice weevil, Sitophilus oryzae, the red flour beetle, Tribolium castaneum, the sawtoothed grain beetle, Oryzaephilus surinamensis, the housefly, Musca domestica, and the German cockroach, Blattella germanica, cineole, l-fenchone, and pulegone.

3.9 Phytosterols Phytosterols are plant sterols. For a long time their biological role was underestimated in mammals. But in 1983 it was found that phytosterols are effective in treating patients with hypercholesterolimic (Bouic, 2001). In a clinical review written by scientist Bouic (2001), it was mentioned that phytosterols have immunological activity in animal models suffering from inflammation and colorectal and breast cancer in vivo and in vitro. Phytosterols are the main component of plant membranes and free phytosterols help in stabilizing phospholipid bilayers in plants as same as the role played by cholesterol in animal cells (Moreau et al., 2002). When consumed by humans phytosterols present in diets, they act as cholesterol-lowering agents (Moreau et al., 2002).

3.10 Organosulphides Garlic is the most important source of organosulphides of various types (Srivastava et al., 1997). Srivastava et al. (1997) studied how organosulfides diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), dipropyl sulfide (DPS), and dipropyl disulfide (DPDS) are effective against benzo(a)pyrene (BP)-induced cancer in mice by modulating enzymes

Methods for Extractions of Value-Added Nutraceuticals  13 involved in BP activation/inactivation pathways. Jakubikova and Sedlak (2005) also studied organosulfides and their mechanism for inducing cytotoxicity, apoptosis, arresting of cell cycle, and oxidative stress in human colon carcinoma cell lines (Caco-2 and HT-29 colon carcinoma).

3.11 Stylbenes Stylebenes, like resveratrol, are phytochemicals responsible for antiaging properties (Baur and Sinclair, 2006). Asian medicine very commonly uses the extract of Polygonum cuspidatum, which is a rich source of stylbenes like resveratrol (Aggarwal et al., 2004).

3.12 Triterpenoids Triterpenoids are secondary metabolites of plant origin and can be obtained from marine and terrestrial plants (Mahato and Sen, 1997). They can also be obtained from nonphotosynthetic bacteria and this created interest among scientists studying evolution. Androgen-associated diseases, such as prostate cancer, acne, hirsutism, benign prostatic hyperplasia (BPH), are serious problems affecting males nowadays (Culig et al. 2002; Wasser and Weis, 1999). BPH affects more than 90% of total males 80–90 years of age.

3.13  Hydroxycinnamic Acid Other important phytochemicals are a class of polyphenols with C6–C3 skelton and hydroxy derivatives of cinnamic acid. Hydroxycinnamic acid compounds are widespread among plant kingdoms and are important as they are an important source for antioxidants. Chen and Ho (1997) studied antioxidant activities of caffeic acid phenethyl ester (CAPE), caffeic acid (CA), ferulic acid (FA), ferulic acid phehethyl ester (FAPE), rosmarinic acid (RA), and chlorogenic acid (CHA), compared to the antioxidant activities of alpha tocopherol and butylated hydroxyanisole (BHT). They performed the rancimat test with all these compounds and the time of lipid oxidation with these compounds was, in decreasing order, CA≈alpha tocopherol >CAPE ≈ RA >CHA > BHT > FA ≈ FAPE. But when lipid substrate changed to corn oil the order of RA > CA CAPE CHA > α-tocopherol > BHT; FA and FAPE antioxidant effect was nil in the corn oil system. Gallardo et al. (2006) studied the hydroxycinnamic acid composition and in vitro antioxidant activity of selected grain fractions. Soluble extracts from rye, buck-wheat, and wheat were used to determine the composition of hydroxycinnamic acid and their antioxidant activities. To determine soluble, insoluble, and free hydroxycinnmic acids composition HPLC-diode aray (DAD) was used. Rye bran and wheat bran fractions has the highest level of hydroxycinnamic acid whereas only traces of the same quantity were observed and noticed in the flour from buckwheat. When tested for antioxidant activities all cereal fraction water extracts have somewhat the same. Among them buckwheat- and wheatgerm-based products have the highest antioxidant acitvites while rye products were the lowest.

14  Chapter 1

3.14 Lignans Lignans are ubiquitous in angiosperms and gymnosperms. Lignans show various bioactive properties, like antitumor, antimitotic, and antimicrobial, especially against viruses, and inhibit some enzymes (MacRae et al., 1989). Olive oil is an important staple diet of Mediterranean region. It is a rich source for lignans as a major component in the phenolic fraction of olive oil (Owen et al., 2000). Phenolic antioxidants were isolated and purified and subjected to structural analysis using several spectroscopic techniques like mass spectrometery (MS) and nuclear magnetic resonance (NMR). It was found that (+)-1-acetoxypinoresinol and (+)-pinoresinol are an important lignan component. In this study they concluded that lignans may act as modulators in the cancer chemopreventive activity (Owen et al., 2000). In mammalian lignan precursors, like secoisolariciresinol diglycoside (SD), the flaxseeds are the richest source for it and have been found to help in decreasing the colon cancer (Jenab and Thompson, 1996). Similar kinds of study were conducted by Rickard (1996), where they studied the dose-dependent production of mammalian lignans in rats and in vitro, from the purified precursor secoisolariciresinol diglycoside in flaxseed. Mammals produce lignans enterodiol (ED) and enterolactaone (EL) by the action of their colonic bacteria on lignans precursors present in their diets. Good sources of lignan precursors are flaxseed and have secoiolariciresinol diglycoside (SDG) (Rickard, 1996). In his study Rickard (1996) studied the various parameters. First was focused on SDG present in flaxseed as not the only source for all the lignans produced; second, SDG produced in mammals was related to the dose intake; and the third was focused on finding any relation between in vitro production and in vivo urinary excretions. Lignan obtained from plants like lariciresinol, matairesinol, pinoresinol, syringaresinol, arctigenin, 7-hydroxymatairesinol, isolariciresinol, and secoisolariciresinol, are metabolized by human fecal microflora so their properties were studied and quantified using HPLC (Puupponen-Pimiä et al., 2005).

3.15 Monophenols Among monophenols the most important one is hydroxytyrosol, which is also called 3,4-dihydroxyphenylethanol (DOPET). It is one of the most important phytochemicals as it is a very strong antioxidant. One of the important sources of monophenols, like hydroxytyrosol, is olive oil. In vivo studies show that hydroxytyrosol have antioxidant activities like quercetin. Human- and animal-based studies proved the bioavailability of hydroxytyrosol; it is absorbed in the intestine on ingestion and becomes metabolized (Goya et al., 2007a). Bulotta et al. (2014) found that hydroxytyrosol, which is a natural antioxidant, prevents the protein damage induced by long-wave ultraviolet radiations in melanoma cells. Long-wave ultraviolet radiations generate free radical and ROS, which in turn damages the skin. They studied the effect of hydroxytyrosol present in olive oil on the viability and redox status of

Methods for Extractions of Value-Added Nutraceuticals  15 HepG2 cell lines and how hydroxytyrosol protects cell lines from oxidative stress caused by tert-butylhydroperoxide (t-BOOH); 10–40 µM HTy treatment for 2 – 20 h prevented the cell damage by tert-butylhydroperoxide (t-BOOH).

3.16 Isothiocynates Raw food from plants like vegetables and fruits are good sources of secondary metabolites of plants origin, which supports good health by adding more nutrition than basic. Best examples are glucosinolates, from Brassicaceae family. Plants use this secondary metabolite for the synthesis of defensive molecules against herbivores by imparting bitter or sharp taste. To date, more than 120 glucosinolates have been identified among plants (Russo et al., 2010). Many studies on animals also showed anticancerous properties of isothiocynates by inhibiting cancer’s initial stages (Kuroiwa et al., 2006) and have anticancerous effects (Hecht, 2000). Phytochemicals can be the potion to tackle cancers and represent very optimistic candidates for chemotherapy and chemoprevention.

3.17 Polyphenols Curcumin is one of the most important members of the polyphenol phytochemical family. It is derived from the rhizome of the Curcuma longa or turmeric. This herb is cultivated mainly in Asian countries on a large scale. Each and every Indian family uses turmeric powder in their meal for flavor and color. Curcumin contains yellow-pigmented fractions of curcumin, demethoxycurcumin, bisdemethoxycurcumin, and cyclocurcumin (Yang et al., 2004).

3.18 Capsaicin As the name suggests, capsaicin is obtained from plants belonging to the genus capsicum and is an active ingredient of many hot and spicy foods. It is one of the components of chili peppers and is an irritant to mammals, responsible for burning sensations to the tissues it contacts. Pain is the outcome of chemical, mechanical, or thermal stimuli, which activates peripheral subgroups of sensory neurons, which are called nociceptors (Fields et al., 1991). Nociceptors transmit information to the brain and spinal cord. These are also very sensitive to capsaicin. Generally, the body responds to pain and releases local inflammatory mediators on exposure to capsaicin to the nociceptor terminals, but prolonged exposure can lead to insensitivity of nociceptor terminals.

3.19  Health-Supporting Properties of Phytochemicals and the Mechanism Behind It Phytochemicals show antimicrobial, antioxidant, and many health-boosting effects (Table 1.3).

Table 1.3: Different types of phytochemicals and their biochemical properties. Molecular Formula Phytochemical

Economical Values

C6H14O1

3-hexenol

It occurs naturally in 1 the flavor and aroma of plants like pineapple. Used as a food additive to add flavor.

HBA HBD Pharmacological Effect 1

Antimicrobial

C10H16

Alpha-thujene

0

0

Antimicrobial

C10H16

Alpha-pinene

Natural organic compound classified as a monoterpene. Monoterpenic in nature.

0

0

NK activity enhancer, antistress, anticancer

C10H16

Camphene

Camphene is used for making fragrances and food additives and fuels. It is also an explosive agent.

0

0

C10H16

Myrcene

Olefinic nature organic compound part of various essential oils and intermediate in the production of various fragrances.

0

0

Reduces plasma cholesterol and triglycerides, prevents hyperlipidemia. Important part of various essential oils, such as turpentine, cypress oil, camphor oil, citronella oil, neroli, ginger oil, and valerian. Antioxidative properties, intermediate of various fragrances, has analgesic effects and antiinflamatory properties, sedatives.

Molecular Mechanism

References

Affects the molecular arrangements of the microbes. Maximum antimicrobial activity was observed with hydrophobic chain length from hydrophilic hydroxyl group. Disturb molecular arrangement of the microbes. Acts on reactive oxygen species; fragrance has alleviating effects.

Kubo and KinstHori (1999)

Inhibits lipoprotein lipase, HMG-Coa reductase.

Increases GSH, CAT, GSH-Px, and Cuzn-SOD. Antiinflamatory actions through prostaglandin E2. Analgesic actions by blocking of nalozone and yohimbine, alpha 2-adrenoceptor stimulated release of opioids.

Cosentino et al. (1999) Kose et al. (2010); Akutsu et al. (2002) Vallianou et al. (2011)

Ciftci et al. (2011)

Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

C10H16

A sweet and pungent smell, water-insoluble, bicyclic monoterpene. CNS depressant.

0

C10H16

Delta 3 carene

Limonene

Colorless cyclic 0 terpene with smell of oranges. It is used in the preparation of renewable cleansers. Biologically d-limonene is more available and commercially obtained by centrifugal separation and steam distillation. It is common in parts of various cosmetic products and medicines and natural falvoring agent. Biofuels.

0

0

Molecular Mechanism

Dry excess fluids, tears, running CNS depressant. noses, excess menstrual flow and perspiration, Antibacterial. Affects molecular arrangement of the microbes. Larvicidal, mosquito repellents, Multiple and novel insecticides, repellents, and target sites, affects antifeedants. the growth rate, reproduction, and behavior of insects. Antifungal and mosquito Multiple and novel target deterrent. sites, affects the growth rate, reproduction, and behavior of insects. Inhibits gamma-interferon and IL-4. Remedies for cerebral disease. Inhibition of acetylcholinesterase Remedy for colds, coughs, Diffused through the entire pleurisy, wind, colic, pulmonary region. rheumatism, and diseases of the urinary organs, skin rashes, wounds, rheumatism, and toothaches. Cosmetic products, used Masks the bitter taste of as flavoring agent. Natural flavonoids. reliever to gastroesophageal reflux disease and heart-burn. Hepatoprotective. Inhibits the malondialdehyde formation. Carminative, diaphoretic, diuretic, antiseptic, and antidepressant.

References —

Massumi et al. (2007) Giatropoulos et al. (2013)

Bhat et al. (2011) Giatropoulos et al. (2013) Aggarwal et al. (2009) Bhat et al. (2011) Bhat et al. (2011)

Sun (2007)

Bhat et al. (2011) Bhat et al. (2011) (Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

C10H16

Commonly used in perfumes and cosmetics, and also as flavoring agent in food. It is used for insect control, especially pine beetle, which is a major threat to pine trees. It does have pleasant smell and used in perfumery, aromatherapy, and herbal remedies. Natural terpene alcohol found in spices and herbs. It is used in toiletries, cleaning agents, perfumes, soaps, shampoos. Linalool is also used for insecticides and in the synthesis of vit-E. Sabinene is natural bicyclic monoterpene. Sabinene contributes to the spiciness of black pepper.

0

Gama-terpinene

C10H14O

Verbenone

C10H18O1

Linalool

C10H18O1

Sabinene hydrate

0

Endo-fenchol

Its terpenic in nature and isomer of borneol. Has great use in perfumery.

References Singh et al. (2004) Wang et al. (2009) Santoyo et al. (2005); Mata et al. (2007)

Cosmetics, flavoring agent. 1

0

Significant enhancement of performance and overall quality of memory.

Antioxidant and antiacetylcholinesterase activities.

1

1

Linalool is anxiolytic.

Acts upon GABA/ benzodiazepine receptor. Soothing smell and effects.

Lopez et al. (2006) Maia and Moore (2011)

Inhibition of acetylcholinesterase. Multiple and novel target sites; affect the growth rate, reproduction, and behavior of insects. DPPH free-radical scavenging activity Affects proteins and lipids of microbial cells.

Bhat et al. (2011) Bhat et al. (2011); Giatropoulos et al. (2013) Bhat et al. (2011) Kotan et al. (2007)

Antimicrobial and good smell.

1

2

Remedies for cerebral disease, antifungal, and mosquito deterrent.

Antioxidant. C10H18O1

Molecular Mechanism

Antifungal, antioxidative,

1

1

Broad-spectrum antimicrobial activity.

Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

C10H18O1

Common ingredient in perfumes, cosmetics, and flavors.

1

Volatile organic sesquiterpenes

0

C15H28

C15H24O1

C13H15NO3 C14H12N2O2

Terpinen-4-ol

Germacrene

8-Hydroxyalphahumulene

Alpha humulene or 0 alpha caryophyllene is monocyclic sequisterpene and found in the essential oil of humulus lupulus. It gives beer a hoppy aroma and has medicinal properties. Ethyl-12-dimethyl-5- Used in medicinal 2 5-Hydroxylinndole- purposes. 3-coarboxylate Beta-carboline-14 propionic acid

1

0

0

1

2

Molecular Mechanism

Antifungal, antioxidative, pleasant smelling agent, common ingredient in perfumes, cosmetics, and flavors. Carminative, diaphoretic, diuretic, antiseptic, and antidepressant. Produced by large numbers of plants for antimicrobial and insecticides actions. Humulene has antiinflamotory properties, and can decrease edema. Anticancerous.

Medicinal uses against viral diseases like dengue and West Nile viral diseases. It is used in preparation of psychedelic drug brews obtained by infusion of various plants.

References Singh et al. (2004) Yao et al. (2005)

Affect the growth rate, reproduction, and behavior of insects. Act as pheromones.

Giatropoulos et al. (2013) Adio (2009)

It inhibits the cancer by Fernandes et al. inhibiting the inflammation (2007) caused by TNF alpha and IL 1beta.

Inhibits virus protease actions.

It prevents the breakdown of dimethyltryptamine in the mammalian gut by blocking the action of monoamine oxidase. It increases the memory, acts as By acting inverse agonist for anxiogenic, and has convulsive benzodiazepine receptor. affects.

Nitsche et al. (2011) Venault and Chapouthier (2007)

Venault and Chapouthier (2007) (Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

C11H12O6

It is found in louts and 6 Vanda teres, Eucomis puncata, and is a secondary metabolite involved in leaves rolling and opening in plants.

4

A terpene ketone in which an (E,E)-farnesyl group is bonded to one of the α-methyls of acetone.

0

C10H30O1

Eucomic acid

Farnesyl acetone

HBA HBD Pharmacological Effect

1

It is used in traditional medicines to treat sore throat and bronchitis and also as paste applied externally on scorpion stings. Eucomic acid and eucomate derivatives, vandaterosides I (2), II (3), and III (4), cellular antiaging properties were evaluated on human immortalized keratinocyte cell line (HaCaT). Antifungal properties.

Antidiabetic. Antibacterial against Propionibacterium acnes. C15H10O5

Apigenin

Coloring agent for wool 5 has chemopreventive role against leukemia, important in metabolism of various drugs as prevent inhibition of various CYP2C9 enzymes.

3

Strong antioxidant, antiinflammatory, and anticarcinogenic properties. Antihepatitis activity. Anti Lassa viral activity, antiviral activity. Antimicrobial activity against bacteria. Metabolisms of various drugs.

Molecular Mechanism

References

Antimicrobial properties and soothing effect.

Sahakitpichan et al. (2012)

It shows their effect on cytochrome c oxidase and increased enzymatic activity or expression without increasing the cellular mitochondrial content.

Simmler et al. (2011)

Nonselective activity against cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX2) whereas 3 (IC(50) 1.88 microg/mL) preferentially inhibited the enzyme COX-2. Antihyperglycemic and insulin secretory activity. Hydrophobic alkyl groups of this long chain alcohol have antimicrobial activity. Able with differential effects in normal versus cancer cells, inhibits IL-1beta and TNF. Inhibits hepatitis virus.

Duru et al. (2003)

Jose and Reddy (2010) Kubo et al. (1994) Patel et al. (2007)

Cushnie and Lamb (2005) Inhibits binding and entry of Liu et al. (2008) Lassa virus into the cells. Affects cellular molecular Konstantiarrangements. nopoulou et al. (2003) Prevents inhibition of Si Dayong et al. various YP2C9 enzymes. (2009)

Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

Molecular Mechanism

References

C16H10O5

Damnacanthal

5

1

Acts as anticancerous substance.

p56lck tyrosine kinase inhibitor.

Faltynek et al. (1995)

C17H14O4

Dihydronortanshinone

It is an anthraquinone and has anticancerous properties. Broad spectrum antibacterial.

3

0

Antibacterial activity.

DNA, RNA, and protein syntheses in microbes were nonselectively inhibited by these compounds. Natural product inhibitors of AChE. Affects cellular molecular arrangements.

Lee et al. (1999)

Used in neural system. C15H10O6

Kaempferol

Natural flavonoid 6 found in many plants and is a good source for anticancerous drugs and cardiovascular diseases.

4

C15H10O6

Luteolin

Luteolin is a flavonoid, 6 with antiskin cancerous and antiallergic activity.

4

C17H23NO4

Anisodamine

5

2

C18H23NO4

Capsaicin

It is also a naturally occurring tropane alkaloid found in some plants of the Solanaceae family. Capsaicinoid and dihydrocapsaicin potent taste and nerve modulators.

4

2

Antimicrobial activity against bacteria. Anticancerous and reduces the chances for cardiovascular diseases, neuroprotective, antiestrogenic, anxiolytic, analgesic, antiallergic, antidiabetic, antiinflamatory. Antiallergic and anticancerous.

Antiinflamatory activity. For the treatment of acute circulatory shock.

Anticancerous and antiinflamatory. Antifungal, topical analgesic, ointments used in making dermal patches, antipsoriasis, antidiabetic, anticancerous, prostate cancer and lung cancer.

Beri et al. (2013) Konstantinopoulou et al. (2003)

Glycosides of kaempferol like kaempferitrin and astragalin.

Inhibition of degranulation and release of TNF-alpha and IL-4 in RBL-2H3 cells.

Sethi et al. (2009)

Anticholinergic and α1-adrenergic receptor antagonist.

Acts on STAT-3 pathway, down regulate cyclin-D1, VEGF. Binds to a protein known as TRPV1.

Aggarwal et al. (2009) Glinski et al. (1991); Lejeune et al. (2003)

(Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

C15H10O7

Quercetin is a 7 flavonoid, used in beer and beverages industries. It is used in making medicines that are antiviral, antiasthamtic, anticancer, antiexzemic, antiinflamatory.

Quercetin

HBA HBD Pharmacological Effect 5

Antiinflammatory, antioxidant, antiviral (HIV), antitoxic, free radical scavenging, cardioprotectant, hepatoprotectant, antitussive, antihemorrhagic. Antiviral, antiasthamtic, anticancer, antiexzemic, antiinflamatory. Anticancerous and antiinflamatory.

Antimicrobial activity against bacteria. C18H23NO4

Lycoremine

Lycorine is a toxic alkaloid.

5

1

C17H19NO5

Piplartine

Natural phytochemicals 6 obtained from pepper obtained in south India and southeast Asia.

0

Antiherpes activity.

Molecular Mechanism

References

Strong inhibitor of HBsAg and HBeAg secretion. Inhibit HIV-1 reverse transcriptase.

Yu et al. (2007); Wu et al. (2007)

Inhibit reverse transcriptase. Jung et al. (2010) PMACI-induced activation of NF-katta B and p38 MAPK in human mast cell line HMC-1. Affects cellular molecular arrangements.

Aggarwal et al. (2009)

Konstantinopoulou et al. (2003)

Kill the herpes-infected cells. Inhibitory effect on the cytopathogenic effect of viral DNA and RNA. Antimicrobial activity Anti bacterial activity by Evidente et al. affecting ascorbic acid (1985) synthesis. Anticancerous and antitumoric. Selectively kill the cancerous cells, inhibits tumor growth with no toxicity toward healthy cells. Very selectively kills the cancer Blocks tumor growth and Raj et al. (2011) cells. metastasis.

Molecular Formula Phytochemical

Economical Values

C20H32O3

It is obtained from 3 Chinese herb Ginkgo biloba and commercially has a strong presence in the herbal market in USA.

Ginkgoneolic acid

C15H12O8

Dihydromyricetin

C18H13NO5

Decumbenine B

C16H12O7

Rahmnetin

C19H14NO4

C21H22O4

Coptisine

Bavachinin

HBA HBD Pharmacological Effect 2

It is a flavanonol 6 used in making hepatoprotective drugs and drugs to counter the affect of alcohol on brain. It’s an alkaloid, used 1 in medicines, alkaloid antitumor agent. It is O-methylated 4 flavonol and is commercially obtained from cloves and used as flavoring agent and in tooth pain relievers.

8

An alkaloid and 0 produces bitter taste used in making medicines for digestive disorders. Antidepressant. Its flavonoid with 1 medicinal valuable activity against cancers.

5

6

7

Anticancerous

References

PI-PLCgamma1 inhibitory activity. These compounds inhibit the multiplication and growth among various cancer cell lines of human origin, but do not affect normal colon cells.

Lee et al. (2004b)

Used in the treatment of the dementia, anxiety, schizophrenia, and insufficient flow to the brain conditions. Antimicrobial. Hepatoprotective effects. Has ability to counter effects of alcohol on brain and fight hangover.

Singh et al. (2010); Ahlemeyer et al. (2001) He et al. (2013) Hase et al. (1997); Hänsel and Klaffenbach (1961)

Antitumor

Xu (2000)

Exhibits topoisomerase II poison activity, as well as catalytic inhibition activity. Broad spectrum. Antimicrobial. Targets the beta hydroxyacyl-acyl carrier proteins. Antimutagenic.

Antidepressants. Used to treat digestive disorders.

4

Molecular Mechanism

Anticancerous.

Affects indirect mutagens like I&, B(alP, AFB1, Trp-P-1, and Glu-P-1). Inhibition of monoamine oxidase A. Inhibitory effects in the proximal and the excitatory effects in the distal stomach. By blocking tumor angiogenesis, as bavachinin, has potent antiangiogenic activity in vitro and in vivo

Zhang et al. (2008); Konstantinopoulou et al. (2003)

Ro et al. (2001) Schemann et al. (2006)

Nepal et al. (2012)

(Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

C15H11ClO7

Delphinidin cloride

—

C20H22N2O3

Perivine

It’s an anthochanidin — primary pigment from plants with strong antioxidant activities. It’s alkaloidic in nature. 2 It’s used in treatment of infectious diseases and cancers.

5

C20H18O5

Methyltanshionate

Phenanthrene quinone derivatives.

0

3

C20H22N2O3

Picrinine

Alkaloidic in nature, commercially used in African nations.

1

5

C22H33NO2

C20H25NO4

Denudatine

Wilsonine

It’s alkaloidic in nature 2 obtained from plant Delphinium denudatum grown in Himalyan region. Has commercial value for treatment of piles, brain diseases, and fungal infections. Alkaloidic 0 phytochemicals used in preparing antitumor medicines.

Molecular Mechanism

References

Antioxidant.

Protects human HaCaT Keratinocytes against UVBmediated oxidative stress and apoptosis.

Faq et al. (2007)

Antimicrobial.

Microbial molecular arrangement disturbances.

Anticancerous activity.

Inhibit proliferation and growth of human breast cancer Effects on microbial molecular distrurbances.

Vijayalakshmidevi et al. (2011) Spelman et al. (2006)

Antimicrobial and bacteriostatic only towards gram positive and Spermicidal activity. Antiinflammatory and analgesic effect.

3

5

Used in treatment of aconite poisoning, piles, toothaches, fungal infections, brain diseases. Vaso relaxing effects.

Anti-Hepa-3B hepatoma cells and also acts against oral epidermoid carcinoma.

Inhibits sperm motility. Inhibited proinflammatory enzymes COX-1, COX-2, or 5-LOX in vitro. Acts on dopaminergic-D2 receptor; brain monoamines.

Baricevic and Bartol (2000) Chattopadhyay et al. (2005) Meena et al. (2001) Rahman et al. (2002); Ahmad et al. (2006)

Is an antiplatelet agent.

Important agent in fight against against (KB) oral epidermoid carcinoma, as well as (Hepa-3B) hepatoma cells.

Kuo et al. (2002)

Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

Molecular Mechanism

References

C20H16N2O4

Camptothecin

6

C21H18NO4

Chelerythrine

C22H26N2O2

Vinpocetine

Quinolinic alkaloidic 2 compounds that inhibit the DNA topoisomerase and used for treatement of cancers. A benzophenanthridine 0 alkaloid used as antimicrobial agent. Semisynthetic derivative 0 of alkaloid vincamine. It has found use as a neuroprotective and cerebrovascular disorders treating agent.

Anticancer activity.

Inhibits the DNA topoisomerase activity.

Takimoto and Calvo (2008)

5

Antimicrobial activity.

Gibbons et al. (2003)

4

Neuroprotective and to treat age-related memory impairment. Antiinflammatory.

Potent, selective, and cell permeable protein kinase C inhibitor. Enhances the cerebral blood flow, which helps memory impairment. Inhibits the upregulation of NF-kB by tumor necrosis factor alpha. Antiinflammatory effect, vasodilation and nootropic.

C20H19NO5

Chelidonine

Alkaloidic in nature used in treatment of nephrotoxicity.

1

6

C20H19NO5

Protopine

0

6

C20H18O6

Asarinin

Alkaloid obtained from opium poppy and commercially used for medical analgesic. It is furofuran lignans and has been important part of food in the Western countries. Used in graft immune modulation and anticancerous properties.

0

6

Helps in treating Parkinson’s disease and Alzheimer’s disease. Antinephrotoxicity; Inhibits activity against antispasmodic and relaxant HuAChE and HuBuChE. activity of chelidonine, acetylcholinesteras, and butyrylcholinesterase inhibitory compounds. Analgesic. Inhibit histamine H1 receptors and platelet aggregation. Graft coating can enhance graft survival.

Beneficial effects of these lignans in breast, colon, and prostate cancer.

McDaniel et al. (2003)

Jeon et al. (2010) Koriem et al. (2013)

Saeed et al. (1997)

Increases the immune Guifang et al. tolerance induced by donor (1999) splenocytes or bone marrow cells combined with asarinin on graft. Hormonal metabolism or Landete (2012) availability, angiogenesis, antioxidation, and gene suppression. (Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

Molecular Mechanism

C16H18O9

Natural polyphenolic compound with chemopreventive activities.

6

Prevents and treats estrogen Noratto et independent breast cancer al. (2009); cells. StacewiczSapuntzakis et al. (2001) Could inhibit RSV directly, Li et al. (2005) extracellularly, inhibition of virus–cell fusion in the early stage, and the inhibition of cell–cell fusion at the end of the RSV replication cycle. Slows the release of glucose Johnston et al. into the bloodstream after (2003) a meal.

Caffeoylquinic acid

9

Chemopreventive effect and laxative effects.

Antiviral activity, antiviral activity against respiratory syncytial virus.

C16H18O9

1-Chlorogenic acid

C16H18O9

Cryptochlorogenic acid

C16H18O9

Neo chlorogenic acid

C16H18O9

Scopolin

C21H26N2O3

Vinacamine

Chlorogenic acid (CGA) is a natural chemical compound, which is the ester of caffeic acid and (–)-quinic acid. Its a natural polyphenolc compound chemopreventive It’s a natural polyphenolc compound chemopreventive. Scopolin is a glucoside of scopoletin by the action of enzyme scopoletin glucosyltransferase. Used in treating infection among plants. Vincamine is a monoterpenoid indole alkaloid used as peripheral vasodilator, which increases the blood flow to the brain.

References

6

9

Antidiabetic and antioxidant.

6

9

6

9

Food, flavouring agents and in pharmaceuticals and antimicrobial. Chemopreventive and laxative effects.

Taste modulators and affects microbial molecular arrangements. Kills cancer cells.

4

9

Antimicrobial, Plant Antiviral kilss TMV

1

5

Used to combat aging and stress.

Antibiotic potentiators or virulence attenuators, reinforcement of the cell wall, biosynthesis of the lytic enzymes, and also production of secondary metabolites like scopolin. Vasodilator, which increases Cook and James the blood flow to the brain. (1981) Used as nootropic agent.

Omar (1992)

StacewiczSapuntzakis et al. (2001) Kuc´ and Currier (1975); GonzálezLamothe et al. (2009)

Molecular Formula Phytochemical C21H26N2O3

Yohimbine

Economical Values

HBA HBD Pharmacological Effect

Molecular Mechanism

References

2

Acts polymorphic to as antagonist to α2A-adrenergic receptor gene for the treatment of the diabetes. Blocks the function of monoamine oxidase enzymes. Yohimbine blocks the pre- and postsynaptic α2 receptors. Inhibited the dendrite outgrowth in melanocytes and reduced epidermal pigmentation also inhibited melanogenesis and reduced the total amount of tyrosinase.

Rosengren et al. (2009); Verwaerde et al. (1997) Millan et al. (2000)

Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, and antiinflammatory and antiautoimmune conditions.

Fiel and Vincken (2006); Thrower (2009); Lambrou et al. (2009); Czock et al. (2005)

5

Stimulant has aphrodisiac effects, antitype two diabetics.

Antidepressants.

Sexual dysfunctionality treatment. C18H16O8

Centaureidine

C21H28O5

Prednisolone

An ortho methylated 3 flavonol obtained from many plants like Brickellia veronicaefolia, Polymnia fruticosa. Commercially used in cosmetics all over the world in skin creams, skin whitening. Derivative of cortisol 3 and synthetically produced as glucocorticoid. Commcercially used for treatment of various autoimmune disorders and inflammatory conditions. Patients with hepatic failure also treated with this.

8

Protects from large number of skin diseases, including melasma, postinflammatory hyperpigmentation, and lentigo.

5

Antiinflamatory and antiautoimmune diseases like uveitis, pyoderma gangrenosum, rheumatoid arthritis, ulcerative colitis, pericarditis, temporal arteritis, and Crohn’s disease, Bell’s palsy, multiple sclerosis, cluster headaches, vasculitis, acute lymphoblastic leukemia, and autoimmune hepatitis. For the treatment of the patients of the hepatic failure.

Adeniyi et al. (2007) Solano et al. (2006); Park et al. (2010); Saeki et al. (2003)

Metabolize prednisone to prednisolone as it is active metabolite of the commercially available drug prednisone. (Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

C18H16O8

Caffeic acid ester with 5 strong antioxidant and medicinal values. Potential anxiolytic and antiviral agent.

Rosmarinic acid

C24H21O5.HCL.H2O Leonurine Hcl

C20H24O7

Diosbulbin A

Commercially obtained from South African plant Leonotis leonurus and is mildly psychoactive alkaloid. It is norclerodane diterpenoid.

HBA HBD Pharmacological Effect 8

5

8

1

7

Ethofenprox

A pyrethroid used in making commercial insecticides.

0

3

References

Inhibits the formation and decomposition of hydroperoxides, superoxide molecules, inhibit COX2, reduces the levels of proinflammatory cytokines and a chemokine, downstream inhibitor of IK kinase-β activity, increased levels of pNF-kB and Cox-2. Anxiolytic. Acts as GABA transaminase inhibitors. Neural acetylcholinesterase Unconjugated inhibitor. rosmarinic acid and its metabolites remain in the bloodstream, bound to human serum albumin and lysozyme. Antimicrobial against Acts against S. pneumonia respiratory tract infections, and haemolytic bone infections, skin infections. streptococci, staphylococci, P. mirabilis.

Frankel et al. (1996); Awad et al. (2009); Pedro et al. (2011)

Antimicrobial.

Prakash and Hosetti (2012) Liu et al. (2011)

Anticancerous.

C22H20N2O4

Molecular Mechanism

Antioxidant, antiviral, antibacterial, anticanerous properties.

Insecticides.

Affects molecular arrangement of microbes. Inhibits proliferation and induce apoptosis in human colon cancer. Neurophysiological effect, affects the sodium channels.

Awad et al. (2009) Pedro et al. (2011)

Pingale et al. (2013); Im et al. (2012)

Becker et al. (2010); Nishimura et al. (1986)

Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

Molecular Mechanism

References

C25H28O3

Epitriptolide

An antiinflammatory isolate of Tripterygium wilfordii.

2

7

Antiinflamatory and anticancerous.

Ma et al. (2007); Xu et al. (2014)

C20H24O7

Ailanthone

Allelopathic chemical used as weedicides, inhibits the growth of other plants.

3

7

Growth inhibitors of other plants, weedicides, Herbicidal effects.

C27H41NO2

Cyclopamine

Steroidal jerveratrum alkaloid used for the treatment of cancers.

2

3

Epitriptolide derivatives as potential anticancer agents were synthesized and tested for their cytotoxicity against SKOV-3 and PC-3 tumor cell lines. Inhibits caretonoids synthesis by inhibiting HPPD enzymes (hydroxyphenylpuruvatedioxygenase) used in carotenoid synthesis and which protects the chlorophyll from damage from sunlight. Lowers the Hh activity, which caused tumor.

C29H48O

Fucosterol

Sterol with antidiabetic and antioxidant properties.

1

1

Anticancerous activity, treatment agent for multiple myeloma, basal cell carcinoma, sarcoma, and so on. Antidiabetic Inhibition of blood glucose level and degradation of glycogen; fucosterolinhibited aldose reductase (AR). Antioxidant properties and It increases the antioxidant hepatoprotective. enzymes hepatic cytosolic superoxide dismutase, catalase, and glutathione peroxidise. Anti HIV-1. HIV integrase strand transfer inhibition Lowers blood pressure. Inhibition of angiotensin convering enzyme and angitensin II receptor blocking. Antibacterial. Molecular arrangements disturbances

C27H45NO2

Hupehenine

Bioactive alkaloid with 2 lowering blood pressure and antiviral properties.

3

C27H41NO3

Peimisine

Bioactive alkaloid.

4

2

Heisey and Heisey (2003)

Beachy et al. (2000)

Lee et al. (2004a); Jung et al. (2013)

Lee et al. (2003)

Zhang et al. (2010) Patten et al. (2013)

Yang et al. (1996) (Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

Molecular Mechanism

References

C27H43NO3

Peiminine

Alkaloidic phytochemicals.

2

4

Treatment of cough.

Zhang et al. (2011)

C24H31NO6

Guan-Fu Base B

Bioactive alkaloids

2

7

C21H20O10

Apigenin 8-C glucoside (Vitexin)

7

10

Acts against oxidative reactive species.

Burda and Oleszek (2001)

C21H20O10

Apigenin 6-C-glucoside (Isovitexin)

Vitexin is an apigenin flavone glucoside, a chemical coupound found in the passion flower. Isovitexin flavonoids is used commercially for the production of antioxidant and antiradicals medicines.

Antiarrhythmic effects, anticardiac arrhythmias, and myocardial contractility. Antioxidant and antiradical activities.

TRPV1 (transient receptor potential vanilloid 1) and transient receptor potential ankyrin 1 (TRPA1). Anticholinesterase activity.

7

10

Carbonyl products, including glyoxal, are reportedly hazardous to human health because of its genotoxicity.

Nishiyama et al. (1994); Ramarathnam et al. (1989)

C21H20O1

Homoorientin

Homoorientin is a flavonoid glycosides.

8

11

Antimycotic properties.

Inhibitory effect of 2 ″-O-glycosyl isovitexin on genotoxic glyoxal formation in a lipid peroxidation system, inhibited xanthine oxidase. Inhibit their growth.

Antiinflamatory and anticancerous activity.

C21H20O11

Cynaroside

Flavones 7-O-glucoside of luteolin and can be found, and have phytopharmaceutical applications.

7

11

Reduces proinflamatory responses and kills oxidant species and shows antiinfllmatory activity. Phytopharmaceutical applications.

Flavonoids increase NOS expression in endothelial cells, inhibit platelet aggregation. Hypocholesterolemic potentials Decreases plasma cholesterol levels.

Dong and Chen (1994)

Turchetti et al. (2005) Schauss (2012)

Negro et al. (2012) Mukherjee (2003)

Molecular Formula Phytochemical C21H20O11 Cyanidine 3-O-glucoside

Economical Values HBA HBD Pharmacological Effect Cyanidin 3-O-glucoside, 8 11 Anticancer, antiproliferative, is an anticancer agent. antioxidant.

Antiacetylcholinesterase and antioxidant. C24H25NO7

8-O-acetyl-excelsine

Alkaloid used in medicines, vitamins, proteins. It is a diterpenoid alkaloid.

—

—

Have anaphylaxis effect, highly nutritious part of Brazil nuts.

C24H39NO7

Fuziline

4

8

Antidepressant.

C23H23N3O5

Topotecan hydrchloride

It is a watersoluble derivative of camptothecin, also called hycamtin. It is used in treatment of cancers.

2

8

Ovarian, lung, and cervical anticancerous agent.

C20H27NO11

Amygdalin (D/R)

Anticancerous glycoside 7 with other name as vitamin B-17.

12

Anticancer.

C22H26O11

Agnuside

Terpenic phytochemicals with anticancer and antiallergic properties.

11

Anticancer and antiallergic.

6

Molecular Mechanism Inhibits ROS production, morphological changes, and alterations in oligonucleosomal DNA fragments. Inhibitory effects on mutagenesis and carcinogenesis in human. Therapeutic effects.

References Moongkarndi et al. (2004)

Enhanced the ratio of phospho-CREB/CREB (cAMP response elementbinding) and BDNF (brainderived neurotrophic factor) protein level in the frontal cortex and hippocampus. Inhibit topoisomerase I, Topotecan intercalates DNA bases and disrupts the DNA duplication machinery; this disruption prevents DNA replication, and ultimately leads to cell death. Induces apoptosis in the prostate cancer cell lines by regulating Bax and Bcl-2 expression. COX-1; antiinflammatory.

Liu et al. (2012)

Nagashiro et al. (2001)

Staker et al. (2002)

Moertel et al. (1982); Newmark et al. (1981) Bellik et al. (2012)

(Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

C22H26O11

Curculigosides are natural phenols that could be useful against β-amyloid aggregation in Alzheimer’s disease.

5

C30H54O4

Curculigoside

25-Hydroxyprotopanaxatriol.

4

11

4

Reduces cerebral ischemia injury.

Molecular Mechanism

Curculigoside A reduced the oxygen–glucose deprivationinduced cytotoxicity and apoptosis, blocked TNF-α-induced NF-kB and IkB-α phosphorylation, and decreased HMGB1 expression. Prevents damages in H2O2-induced reduction osteoblasts. of differentiation markers, such as alkaline phosphatase, calcium deposition, and Runx2 level was significantly recovered due to CUR. CUR prevents from H2O2-induced stimulation of extracellular signal-regulated kinase 1/2, and nuclear factor-kB signaling and the inhibition of p38 mitogen-activated protein kinase activation. Circuligoside attenuates human Curculigoside can inhibit umbilical veins endothelial cell H2O2-induced injury injury. in human umbilical vein endothelial cells, pretreatment with curculigoside decreased the activity of caspase-3 and p53 mRNA expression, which was known to play a key role in H2O2-induced cell apoptosis.

References Jiang et al. (2011)

Wang et al. (2012)

Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

C22H22O12

Isorhamnetin-3-Ogalactoside

Natural flavonoid used 7 to tackle inflammation, ROS, phagocytosis.

12

Inhibitory effect on ROS in PMNs, prevents oxidative burst of PMNs and also protect membrane damage by lipid peroxidations.

C22H22O12

Isorhamnetin-3-Oglucoside

Flavonoidic in nature used in various medicines.

12

Treatment of injured or inflamed arteries.

C22H22O12

Neptrin

—

Used as anticold and anticough.

C28H46O6

Brassinolide

Important components — of various Chinese medicines. A steroidal lactone used 4 as growth promoters.

6

Responses similar to IAA were elicited by Brassinolide in plants.

C35H52O4

Hyperforin

Hyperforin is a prenylated phloroglucinol derivative, produced by some of the members of the plant genus Hypericum. It accumulates in oil glands, pistils, and fruits, probably as a plant defense against herbivory.

4

Antidepressant, antixiolytic.

7

1

Molecular Mechanism

References

Used to tackle dangerous agents released during the inflammations, ROS. Tackeling phagocytosis caused by PMNs, poly morphonuclear neutrophils, archidonic acid metabolites. Quercetin acts on the inflamed and injured arteries by activated macrophages. Macrophages are the targets in human atherosclerotic arteries. It resolves the phlegm and prevents coughing and wheezing. Has role in hypocotyl hook opening, elongation of maize mesocotyl, fresh weight increase in Jerusalem artichoke (2,4-D used pea epicotyls, azuki bean epicotyl sections) and pea epicotyl sections. Reuptake inhibitor of monoamines like norepinephrine, serotonin,, dopamine. Reuptake inhibitors of GABA and glutamate. Modulates release of acetylcholine release in himppocampal region. Also help in release of acetylcholine release from striatum.

Zielinska et al. (2001)

Kawai et al. (2008)

Xia (1998)

Mandava et al. (1981)

Buchholzer et al. (2002); Kiewert et al. (2004)

(Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect Topical antibiotic.

Anti-Alzheimer’s disease.

Sexual problems.

C40H56

Lycopene

C29H44O9

Rhodexin A

C40H56

Beta-carotene

Carotenoid found in 0 tomatoes and many fruits. Carotene with no Vitamin-A. Carotenoid in nature 5 used in anticancerous medicines. Natural lipid 0 antioxidant.

Molecular Mechanism

References

Affect molecular arrangements of microbes like MRSA. Procognotive, find use in the treatment of Alzheimer’s disease. Effective against the premature ejaculation.

Reichling et al. (2001)

Anticancerous effects.

Acts as antianjgiogenic and proapoptopic, also anticlastogenic.

Antidepressant.

Acts upon sigma and D2 receptor. Inhibits COX1 and 5-LO. PSA level.

0

Anti-inflamatory effects. Anticancerous properties and prevent skin damage.

9

Anticancerous.

0

Lipid antioxidant, Good radical-trapping anticancerous (in on smokers). antioxidant behavior.

Cytotoxic activity against leukemia cell K562.

Kim and Chancellor (2008) Quiney et al. (2006); MartínezPoveda et al. (2010); Sun et al. (2011)

Ilic et al. (2011); Rizwan et al. (2011) Umebayashi et al. (2003) Mayne (1996); Burton and Ingold (1984); Peto et al. (1981)

Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

C30H18O10

Amentoflavon

Biflavonoid, found in 6 various plants used in various antimalarial and metabolism of various drugs.

10

C31H24O10

Sikokianin A

Biflavonoid used in various medicinal uses.

10

C32H44O8

Cucurbitacin E

It is an oxidated steroid 3 consisting of tetracyclic triterpenes.

5

8

Molecular Mechanism

References

Antimalarial and leishmanicidal Targets the M1 alanyl and Thivierge et al. activity. M17 leucyl aminopeptidase. (2012); Kunert et al. (2008) Helps in drug metabolisms. Inhibitior of CYP3A4 and CYP2C9 enzymes involved in drug metabolisms. Anticancer activity. Inhibits the fatty acid Lee et al. synthatase enzymes. (2013); Wilsky et al. (2012) Antimicrobial. Antimitotic and antifungal. Yang et al. (2005) Antimalarial. Inhibitory affect against malaria. Antiviral activity. Shows anti-HBV effect Yang and Chen HBsAg secretion. (2008) Antiinflamtory activity. Inhibition of cycloAbdelwahab et oxygenase, ROS and RNS al. (2011) macrophages, produces cytokines, reactive nitrogen species, growth factors by the activation by chemical mediators. Inhibition of the tumor. Inhibits tumor angiogenesis. Chen et al. (2012) Antioxidant properties. Scavanges the free radicals. Tannin-Spitz et al. (2007) Cytostatic activity. Inhibits the cell mitosis during the S and M phase. Also disrupts the cytoskeleton actin. Hepatoprotective. Reduces the GPT, GOT, Chen et al. ALP, TP, and TBIL. (2012) Antimetastatis. Inhibits adhesions of cancer Chen et al. cell acts upon collagen (2012) type 1. (Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

Molecular Mechanism

References

C32H22O10

It is biflavone. Used in making medicines.

4

Inhibitor of group II phospholipase A 2.

Kwak et al. (2002)

Inhibition of virus replication. Stimulates hair growth.

Hayashi et al. (1992) Gallwitz et al. (2010) Liu et al. (2007)

C32H22O10

Ginkgetin

Isoginkgetin

A natural biflavonoid used in various medicinal formulations for antidibeties, antioxidants, and hair growth properties.

4

10

10

Potent antiarthritic activity, analgesic activity and inhibit arthiritis. Antiherpes. Fight baldness. Antidiabetic.

Antioxidant.

Antitumor.

C15H12O5 C3H23N3O5

Naringin

Citrus bioflavonoid, flavanone glycoside.

8

14

Affects the drug uptake.

Antineuropathic. Protective effect.

C27H30O14

Rhamnosylvitexin

Flavonoid used in medicines.

9

14

Anticancer.

Rhoifolin

Flavone glycoside, or flavones, a type of flavonoid found in canton lemon, grapefruit.

8

14

Anticancerous and antiproliferative.

Enhances adiponectin secretion from differentiated adiposarcoma cells via a novel pathway involving AMP-activated protein kinase. Scavenges the free radicals. EllnainWojtaszek et al. (2003) Splicing inhibition is the O’Brien et al. mechanistic basis of the (2008) antitumor activity of isoginkgetin. Naringin inhibits some drug- Bailey et al. metabolizing cytochrome (1998) P450 enzymes, including CYP3A4 and CYP1A2. Reduced diabetes-induced Kandhare et al. neuropathy. (2012) Protective effects on Kumar et al. cognition and oxidative. (2010) Antiproliferative and Way et al. apoptotic effects in human (2009) breast cancer. Anticancerous effect on Eldahshan hepatocellular (Hep G2), (2013) colon (HCT-116), and fetal human lung fibroblast (MRC-5).

Molecular Formula Phytochemical C27H30O10

C27H30O15 C33H52O8

HBA HBD Pharmacological Effect

Vitexin-4

Apigenein flavones 9 glucoside found in pearl millet, passion flower and so on. These are O-methylated 9 Vitexin-2′′-Oflavonoid rhamnoside Diosgenin glucoside Plant phytochemicals 4 used in various medicines.

C33H52O8

B3-procyanidin

C32H45NO10

O-Benzoylmesaconine

C27H30O15

Kaempferol 7-neohesperidoside

C30H26O13

Procyanidin

C37H42N2O6

Economical Values

Dauricinoline

Used in medicines for hair growth. Aconitine alkaloids.

Phenolic compounds used in various medicines. Member of proanthocyanidin class of flavonoids.

Alkaloids used in various psychotropic medicines. One of important crude drugs exported by China.

References

14

Responsible for causing goiter.

It inhibits enzyme thyroid peroxidise and contributes goiter.

Gaitan (1990)

14

Anticancer

8

Antioxidant.

Strongly inhibited DNA synthesis in MCF-7 cells. Neutralizes ROS.

Antitumor.

Antiproliferative activities.

Antihypercholesterolemia and atherosclerosis. Antibald activity.

Inhibits intestinal absorptions of cholesterol. Hair growth stimulant.

Ninfali et al. (2007) Araghiniknam et al. (1996) Carvalho et al. (2010) Malinow (1986)

Antiburn infections caused by HSV type 1 and candida albicans.

Inhibits the cytokine production by various type2 T cells.

Analgesic/antiinflammatory/ antipyretic activity. Antiinflammatory

Prevent growth of cells.

10

12

4

11

9

15

10

13

2

Molecular Mechanism

8

TNF, IL-1beta, caspases, and specifically targets JAK3 of hemopoietic cells. It has antioxidant capacity, that Neutralizes free radicals. is, oxygen radical absorbance capacity (ORAC). Have antioxidant properties higher than vitamins. Help in smoothing blood Suppress production of vessels. protein endothelin-1 Antidepressants. MAO inhibitory. Find use for treatment of Ability to modulate ca2+ allergy, arrhythmia and uptake and several k+ inflammation. channels. It also affects human-ether-a-go-gorelated gene (HERG) channels.

Benavides et al. (2006) Kobayashi et al. (1998)

Murayama (1998) Aggarwal et al. (2009)

Corder et al. (2006) Xu et al. (2010) Zhao et al. (2012)

(Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

Molecular Mechanism

References

C37H42N2O6

Daurinoline

2

8

Find use for treatment of allergy, arrhythmia, and inflammation.

Daurisoline

2

8

Used in the treatment of inflammation, allergy, and arrhythmia.

C37H42N2O6

N-desmethyldauricine Hesperdine

2

8

Antitumor.

8

8

Anti-inflammatory.

Ability to modulate ca uptake and several k+ channels. It also affects human-ether-a-go-go-related gene (HERG) channels. Ability to modulate ca2+ uptake and several k+ channels. It also affects human-ether-a-go-go-related gene (HERG) channels. Immunoregulatory activity of PE2. Inhibits both acute and chronic inflammations. Interact with gut microflora and undergo better absorptions. Apoptotic effects on the human colon cancer cells by acting upon caspase3. Antioxidant effects because of vasodilating effects.

Zhao et al. (2012)

C37H42N2O6

Alkaloids used in various psychotropic medicines. One of important crude drugs exported by China. Alkaloids used in various psychotropic medicines. One of important crude drugs exported by China. A new phenolic dauricine alkaloids. Flavanones used in various human disorders treatment.

Prevents phospholipid hydroper-oxidations. Inhibition of cAMPphosphodiesterase (PDE). Neutralizing the ROS.

Yao et al. (2004) Dallas et al. (2008) Kwon et al. (2009)

Growth inhibitory effects of Q was due to a blocking action in the G0/G1 phase Inhibits cell growth.

Chen et al. (2006); Ranelletti et al. (1992) De Wet et al. (2009); Ono et al. (1994)

C23H23N3O5

Enhances the bioavailability of flavonoids Anticancerous.

C37H42N2O6

Liensinine

Alkaloids with antioxidant effects and phytochemicals effects. Flavones with high health benefits.

2

8

Antioxidant.

C28H34O15

Neohesperidin

2

8

Rhodiosin

Flavonol glycoside.

2

8

C23H23N3O5

Quercetin 3-rutinoside

2

8

C23H23N3O5

Cycleanine

Flavonoids used in various human medicines. Alkaloids with anticancer activity.

Increases antioxidant capacity, acts as antioxidant, lipolytic affects inhuman body fat adipocites. Antioxidant and helps in treatment of diabetes mellitus, cancer, Alzheimer’s disease. Cancer inhibitory.

C27H30O16

0

8

Anticancer activity against various human cancer cell lines.

2+

Zhao et al. (2012)

Shan et al. (2006) Guardia et al. (2001) Selma et al. (2009); Yao et al. (2004) Yao et al. (2004) Lee et al. (2005)

Molecular Formula Phytochemical C36H62O8 Ginsenoside Ck or Rh2

Economical Values Steroid glycosides, and triterpene saponins.

HBA HBD Pharmacological Effect 6 8 Anticancerous and immunomodulating.

C29H34O15

Pectolinarin

Flavonoid glycosides.

7

C38H42N2O6

Tetrandrine

A bis-benzylisoquinoline 0 alkaloid.

15

Anticancerous and prevent hepatic injury.

8

It does have antiinflamatory properties. Anticancerous.

C31H40O15

Martynoside

Phenylpropanoid glycosides.

7

15

C32H46O16

Secoisolariciresinol diglucoside

Plant lignin.

10

16

C42H72O14

Ginsenoside Rf

Found in traditional oriental medicinal plants. It is a type of saponins.

2

2

Helps in retardation of skeletal muscle fatigue. Anticancerous, cytotoxic, and antimetastatic. Estrogenic and antietrogenic properties. Reduces serum cholesterol and hypercholesterolemic atherosclerosis. Antioxidant activities.

Antinociception activity.

Molecular Mechanism Inhibition of tumor angiogenesis and metastatis. It has analgesic, antiinflammatory activity and prevents spreading of cancer.

References Sato et al. (1994)

MartinezVazquez et al. (1998); Lim et al. (2008) Prevents injury to hepatic Yoo et al. cells by being antioxidant. (2008) Reduces the inflammation Wong et al. induced by Interlukin-1, TNF (1992) and PAF Induces Cell growth arrest Lee et al. (2002) and apoptosis. Effects muscle contractility. Liao et al. (1999) Acts on cancer cells. Liao et al. (1999) Activate estrogen receptor Papoutsi et al. isoforms ERα and ERβ (2006) Lignans are platelet activating Prasad (1999); factor receptor antagonists and lowers the production of oxygen free radicals. Antioxidant property is also responsible for reduction of hypercholesterolemic atherosclerosis. There was reduction in serum cholesterol, LDL-C, and lipid peroxidation product while an increase in HDL-C and antioxidant reserve. Ginsenosides Rf inhibits Mogil et al. Ca2+ channels in mammalian (1998) sensory neurons. (Continued)

Table 1.3: Different types of phytochemicals and their biochemical properties. (cont.) Molecular Formula Phytochemical

Economical Values

HBA HBD Pharmacological Effect

C45H72O17

Gracillin

It is a type of saponin 9 and is used in medicinal products.

17

C45H73NO16

Solasonine

It is a type of glycoalkaloid.

10

17

Antileukaemic alkaloids 5 and has huge market for leukemic patients. Generation of gian spermatogonial cells, which can be controlled by hormone. It’s a triterpenoid 11 glycoside.

18

Steroidal glycosides or 3 cholestane glycosides hold potential as phytochemicals based drugs.

3

C46H56N4O10.H2SO4 Vincristine sulfate

C48H78O17

Saikosaponin C

C46H72O19

Saundersioside A

HBA, Hydrogen bond acceptor; HBD, hydrogen bond donor

18

Molecular Mechanism

References

Expectorant, antiinflammatory, vasoprotective, hypocholesterolemic, immunomodulatory, hypoglycaemic, molluscicidal, antifungal, antiparasitic and many others properties. Methyl protogracillin is good in the treatment of cancer of urinary bladder, cervical carcinoma, carcinoma of and renal tumor. Pancreatic lipase inhibitor, suppresses blood triacylglycerol level, inhibits adipogenesis. Antiproliferative activities against human colon (HT29) and liver (HepG2) cancer cells. Antileukaemic alkaloids.

—

Podolak et al. (2010)

Induces ERα expression, inhibits p38 MAPK, decreases expression of C/ EBPα, LPL, PPARγ and leptin.

Hu and Yao (2001); Vermaak et al. (2011)

Inhibition of growth of cancer cells.

Lee et al. (2004a,b)

By probably affecting spermato-genic mitosis.

Stanley and Akbarsha (1992); Steinberger (1971)

Saponins are antiinflamatory, immunomodulatory, hepatoprotective, antitumor and antiviral activities, antimicrobial, antihepatitis B virus. Antileukemic.

Induction of apoptosis through the activation of caspases 3 and 7, which subsequently resulted in poly-ADP-ribose-polymerase (PARP) cleavage. Potent cytostatic activity, induction of apoptosis by cell morphology and DNA fragmentation.

WHO (1998); Shao et al. (1999); Uckan et al. (2005); Chiang et al. (2003) Kuroda et al. (1997)

Methods for Extractions of Value-Added Nutraceuticals  41

Figure 1.1: Oxidative Stress Circle (Ilie and Margina˘, 2012).

Oxidative stress (Fig. 1.1) is the outcome of imbalance between the amount of prooxidant and antioxidant; the amount of prooxidant is high, which leads to the generation of ROS (Sies, 1991). There are many free radical productions during normal biochemical reaction that a cell undergoes. Most of them are centered on oxygen and halogens and are sulfurbased (Halliwell and Gutteridge, 2007a). Most of the endogeneous free radical species are nitric monoxide (NO), singlet oxygen (1Og+O2), hydroxyl (OH), and superoxide (O −2 ). Others are peroxynitrite (ONOO–) and hydrogen peroxide (H2O2), which are responsible for generating free radicals in the living cells by getting involved in various chemical reactions (Halliwell, 2006). Various studies have indicated that the formation of direct DNA oxidants that are the derivative of hydrogen peroxide is a cell metabolism-dependent process (Imlay et al., 1988). This DNA oxidant is generated in the presence of reducing equivalents and any source of iron ions (FeCl3, FeSO4), and initiates a Fenton reaction, where hydrogen peroxide is reduced by ferrous iron to a reactive radical and this then affects various biomolecules of the cells (Fig. 1.2).

4  Disturbing the Lingocellulosic Arrangement Special arrangements of lingocellulosic components make plant biomass resistant for degradation to biological and chemical agents. Lingocellulosic component pretreatment strategies and conditions also vary with the type and part of plants used. The pretreated bark

42  Chapter 1

Figure 1.2: Damage to Cells and Biomolecules by Free Radicals.

of poplar trees and corn leaves with dilute acid but with the same method was not suitable for corn stalks and sweet-gum bark; instead, the enzymatic pretreatment strategy was more suitable (Donghai et al., 2006). For biological degradation of lingocellulosic materials, crystallinity, hemicelluloses-lignin percentage, free accessible area, degree of acetylation and polymerization of hemicelluloses, and celluloses are major factors (Wyman, 1996). There are various kinds of interactions that take place between the components of lignocelluloses. The main types of bonds that exist are hydrogen bonds, ester bonds, carbon-to-carbon interaction, and ether bonds, details of which are provided in Table 1.4.

4.1  Pretreatment of Lingocellulosic Biomass Pretreatment of plant biomass can be done by physical, chemical, and biological methods. Pretreatment of biomass like Pinus robxburghii forest wastes helps in the bioavailability to enzymes and biodigestibility in bioethanol production. 4.1.1  Physical pretreatment Physical pretreatment is generally done to reduce the size of lingocellulosic waste material or biomass by involving grinders, millers, or chippers either singularly or in combinations. Reduction of size also reduces the crystallinity of the biomass. Millers are used when the size Table 1.4: Different types of bonding among lingocellulosic components (Faulon and Hatcher, 1994). S. no.

Types of Bonds

Components

Linkages Type

1. 2. 3. 4. 5. 6. 7.

Hydrogen bond Carbon to carbon bond Ether bond Ester bond Ether bond Ester bond Hydrogen bond

Cellulose Lignin Lignin and hemicelluloses Hemicelluloses Cellulose-lignin, hemicelluloses-lignin, Hemicellulose-lignin Cellulose-hemicellulose, hemicelluloses-lignin

Intrapolymeric Intrapolymeric Interapolymeric Intrapolymeirc Interpolymeric Interplymeric Interpolymeric

Methods for Extractions of Value-Added Nutraceuticals  43 of biomass is to be reduced up to 0.2–2.0 mm, similar to the effect of grinders. Chippers reduce the size up to 10–30 mm (Sun and Cheng, 2002). But it is important to note that the power consumptions are related to the size reduction of the biomass (Cadoche and López, 1989). 4.1.1.1 Pyrolysis

In this process biomasses are thermochemically decomposed at very high temperatures in the absence of oxygen. It is the process that is irreversible and involves both chemical and physical changes. Pyrolysis of biomass rich in organic components generates gas and liquid byproducts while a solid is left richer in organic carbon, called char, or sygnas and biochar. Pyrolysis of wood or plant biomaterial is done at temperatures between 200 and 300°C, because at low temperatures the products are less volatile (Kumar et al., 2009). Fan et al. found that mild acid hydrolysis of the product obtained from pyrolysis resulted in more than 80% conversion of cellulose to reducing sugar while 50% glucose generation, finally (Jia et al., 1996). Though the process of pyrolysis was carried out in the absence of oxygen, the same was enhanced in the presence of oxygen in the case of biomass. 4.1.1.2  Steam explosion

Steam explosion of biomass is the most common and preferred method for pretreatment of biomasses. Steam explosion involves first the increase of steam pressure up to or more than 15 psi at 120–260°C for a few seconds, and then pressure is reduced at once, which leads to the explosion of the biomass material. Steam explosion improves hydrolysis of hemicelluloses. Steam explosion causes conversion of lignin and degradation of hemicellulose, benefiting the overall conversion. It is believed that hemicellulose undergoes hydrolysis by the action of acetic acid and other acids produced due to high temperature and pressure. Compared to steam exploded and untreated poplar chips, enzymatic hydrolysis was better up to 90% in the case of pretreated chips while it was only 15% for untreated chips (Sun and Cheng, 2002). It is believed that lignin is not fully removed from the fiber; instead it gets redistributed on the biomass or fiber surface because of depolymerization after being melted at high temperatures, but sudden lowering of temperature due to the release of steam (Li et al., 2009). This leads to an increase in the surface area of action for the enzymes (Duff and Murray, 1996). It’s also well known that water at high temperature can act as acid (Wyman et al., 2005). In the addition of acid, like H2SO4, or CO2, or SO2 up to 3% in the steam explosion, the time period and temperature can be reduced and less inhibitor formations and more hemicelluloses removal (Ballesteros et al., 2006). The factors that affect the efficacy of steam explosion pretreatment are the size of biomass, residence, or holding time, moisture content and temperature (Duff and Murray, 1996). Steam explosion is a cost-effective technology as tested on pilot scale for hard wood and agricultural waste but not for soft wood (Sun and Cheng, 2002). While a limitation of this technology is that xylan gets destroyed, incomplete destruction of matrix-holding lignin and carbohydrates, and, most

44  Chapter 1 importantly, generation of inhibitors, inhibit growth of microbes that are used in further downstream processing (Mackie et al., 1985). 4.1.1.3  Ammonia fiber explosion

In this strategy biomass is physicochemically treated, where biomass or lignocellulosic waste are exposed to liquid ammonia at temperatures above 90°C. In this process biomass is treated with ammonia solutions up to 1–2 kg/kg weight of dry biomass at temperatures of 90°C or more for 30 min holding time (Kumar et al., 2009). Ammonia recycle percolation is another technique in which ammonia solution 10%–15% in water is allowed to pass from biomass at temperatures of 140–180°C, with fluid moving with a velocity of approximately 1–2 cm/min and has a holding time of 14 min. The ammonia is obtained and separated, which is then further recycled. Liquid ammonia solution reacts with lignin and is responsible for breaking the polymer linkages of lignin and carbohydrates. This process holds the advantage of not producing inhibitors, which is a water-saving method (Galbe and Zacchi, 2002; Kumar et al. 2009). 4.1.1.4  Carbon dioxide explosion

Carbon dioxide explosion is cheaper than ammonia explosion and requires less temperature for treatment compared to steam explosion. Supercritical fluids are gases compressed to have liquid like density at temperature more than their critical point (Kumar et al., 2009). The advantages of supercritical fluids are many, like CO2 releases carbonic acid, which increases the rate of hydrolysis of substrate. The molecules of carbon dioxide are the same size as that of ammonia and water so it can easily penetrate the same way. Low temperature lowers the decomposition of monomeric sugars by the acids. Supercritical carbon dioxide explosion also increases the surface and are accessible to enzymes of microbes.

4.2  Chemical Treatment 4.2.1 Ozonolysis Lignin content can be reduced by the use of ozone and leads to an increase of digestibility of the biomass. Ozone does not produce inhibitors so it’s better than other chemical methods. Ozone has been used to degrade various kinds of biomass, like wheat straw, bagasse, peanut, pines (Ben-Ghedalia and Miron, 1981). When used to pretreat poplar sawdust it was found that enzymatic hydrolysis increased up to 50% and lignin content decreased to 8% from 29% (Vidal and Molinier, 1988). Less inhibitor generation at room temperature and atmospheric pressure all make this process advantageous over other processes. To prevent harm to the environment used ozone is then treated with a catalytic bed or simply by increasing the temperature it can decompose the ozone (Quesada et al., 1999). Now, most of the ozonebased pretreatment of biomass is done with hydrated fixed bed because it leads to more

Methods for Extractions of Value-Added Nutraceuticals  45 oxidation of the same better than H2O solution suspension or 45% acetic acid solutions (Vidal and Molinier, 1988). 4.2.2  Acid hydrolysis Acids like H2SO4 and HCl are used in treating lignocellulosic biomass for enhancing enzymatic hydrolysis and the release of more sugar. Acids have toxic, corrosive, hazardous natures so special types of reactors are required, which are resistant to corrosion. So, to make the process feasible at a commercial level, recovery of the acid used is required (Sun and Cheng, 2002). For acid pretreatment of biomass either dilute or strong acids are used. Dilute acid hydrolysis is done with H2SO4 (4%), as it is economical and effective. Furfural is the product treatment of cellulose with dilute acid (Zeitsch, 2000). Dilute acid acts on the biomass to convert hemicelluloses to xylose and other sugars and then to furfural (Weil et al., 1997). H2SO4 recovers almost 100% of hemicelluloses and high temperature favors the digestibility of cellulose in the residual solids (Mosier et al., 2005). There are two types of dilute acid pretreatment methods involving high temperature and others at low temperature. The high temperature process works at (T >160°C), with continuous flow for biomass in a 5%–10% of the substrate to weight of overall mixture ratio. While temperatures below 160°C and substrate loading to overall reaction mixture in a ratio of 10%–40% in a batch process makes the process of low temperature dilute acid pretreatment (Brennan et al., 1986). Acid pretreatment can be used on a wide range of substrates like hard woods to agricultural residues and grasses (Kumar et al., 2009). But there are some drawbacks associated with acid pretreatment involving high-energy consumption. Equipment configurations, corrosion, negative impact on enzymes on later-on stages, and a large amount of water consumption in upstream and downstream processing makes the process costly even more than steam explosion and AFEX (Kumar et al., 2009). 4.2.3  Alkaline hydrolysis Depending on the percentage of lignin in the lingocellulosic biomass some masses can also be used (McMillan, 1994). Alkali pretreatment is carried out at low temperatures and pressure compared to other technologies but the order of pretreatment is of hours or maybe days. Alkali pretreatment produces fewer sugars compared to acid pretreatment. Basic reagents like hydroxides of calcium, potassium, sodium, and ammonium are used for alkali pretreatment. Out of these four, though sodium hydroxide is studied more, but on the basis of cost, hydroxides of calcium are more effective and the least expensive of all. Recovery of calcium from calcium carbonate from the used solution is also very easy by using carbon dioxide and regenerates it to calcium hydroxide by using lime-kiln technology. Lime pretreatment removes amorphous portions like lignin and hemicelluloses and increases the crystallinity index. Enzymatic pretreatments are affected by the structural changes occur due to the pretreatment (Kim and Holtzapple, 2006).

46  Chapter 1 4.2.4  Oxidative delignification Oxidative delignification can be achieved by use of peroxidase enzyme in the presence of hydrogen peroxide (Azzam, 1989). Azzam (1989) found 50% lignin removal and almost all hemicelluloses solubilization at 2% hydrogen peroxide. Bjerre and coworkers used wet oxidative alkaline hydrolysis-based delignification at 170°C for 5–10 min and noted 85% of total cellulose being converted to glucose (Ahring et al., 1996). Polysaccharide can be made more susceptible to enzymatic hydrolysis after performing wet oxidative pretreatment with the addition of base and making maximum hydrolysis of polysaccharides (Kumar et al., 2009). 4.2.5  Organosolv process Organosolvation process utilizes either an organic solvent or an aqueous organic solvent mixed with inorganic acid catalysts like HCl or H2SO4. This pretreatment strategy breaks down the bonds between internal lignin and the hemicelluloses. Solvents preferred in this process are methanol, ethanol, acetone, triethylene glycol, acetone, and tetrahydrofurfuryl alcohol (Chum et al., 1988).

4.3  Biological Pretreatment Each process has its own requirement of energy and cost. Processes like physical, mechanical treatment along with thermochemical pretreatment require abundant energy for processing the biomass. Pretreatment processes involving the use of whole microbes or enzymes are called biological pretreatment processes. Bacteria or fungi are involved, which are less energy consuming and are safe to the environment but efficient in lignin removal from the plant biomass (Okano et al., 2005). Biological degradations and hydrolysis of lingocellulosic biomass for pretreatment and posttreatment can be done by the use of cocktails of enzymes, like keratinase, cellulase, amylase, protease, and lipase. Pretreatment of food wastes for sugar production and then for fermentation of that sugar for ethanol production was carried out. Ethanol production from food waste was produced by using a lab scale fermenter after the pretreatment by using a mixture of enzymes like carbohydrase, glucoamylase, cellulase, and protease. Fermentation was carried by using enzyme carbohydrase and microbes Saccharomyces cerevisiae. 4.3.1  Enzyme-based biological hydrolysis The use of alternate substrates as the raw material for the production of enzymes and then produced enzymes are employed for the production of alcohol is a good idea. Kitchen waste was used for the production of ethanol and for rearing of enzymes used in the biofuel production by Wang et al. (2010). To obtain enzyme cocktails different substrates were used and one of them was forest wastes and kitchen wastes. But the problem of low porosity of

Methods for Extractions of Value-Added Nutraceuticals  47 kitchen waste was overcome by the addition of paddy husk and corn stover. Corn stover was found to be more effective than paddy waste and was used with kitchen waste with a ratio of 1:3.75 (Wang et al., 2010). The production of enzyme cocktails can be done by growing all enzyme producers together. There have been a number of reports supporting cocultivation of microbes for the release lignocellulosic waste degrading enzymes (Vats et al., 2013). Basidomycetes consortium capable of producing cellulase, xylanase, and peroxidases has been employed for lignocellulosic waste degradation (Baldrian et al., 2005, 2011). Consortia prepared by Haruta et al. (2002) also degraded many cellulosic substances, like filter paper, printing paper, cotton, and rice straws, which were 60% degraded by their consortia within 4 days. Microbial consortia prepared by Sarkar et al. (2011), capable of producing enzyme with concomitant activity, were used to degrade kitchen wastes. In their study they noted a 55%–65% decrease in the volume of the kitchen wastes, with less time of degradation and reduced foul smell.

5  Mathematical Modeling To disturb the lingocellulosic structural framework, pretreatment of lignocellulosic biomass is a must to ease the extraction of value-added products. Biological pretreatment methods for lignocellulosic biomass wastes generated from industries are better than chemical and physical treatment methods, being ecofriendly, specific, and producing less side products (Table 1.5). Physicobiological pretreatment methods like steam explosionbased enzymatic pretreatment process is significantly influenced by factors like steam pressure, ratios at which each enzyme used and incubation time with solvent system, incubation time during steam explosion, steam explosion pressure, and solvent system volume. Practically, optimizing “one variable at a time” approach disregards the complex interactions among parameters. Out of various new statistical optimization methods, response surface methodology (RSM) combines mathematical and statistical techniques for analyzing problems with several independent variables having control on a dependent variable. One parameter at one time, based optimization cannot study the combined effect of all variables.

6 Conclusions History has witnessed high numbers of loss to human life either by war or to diseases. Havoc created by infectious diseases like plague, tuberculosis, cholera, and malaria have pivotally shaken the course of history. Challenges posed by new emerging diseases is no stranger to humans living in any part of world. The present world is a global village and millions of people travel across one country to another, where large populations provide all possible opportunities for contagious diseases to spread as epidemics and pandemics. Stressful lifestyles, adulteration in the food, rising antibiotic resistance among microbes,

48  Chapter 1 Table 1.5: Comparative analysis of various extraction methods employeda.

S. No.

Method

Solvents Used

1.

Soxhlet extraction

2.

Sonication

3.

Maceration

Methanol, ethanol, mixture of water or alcohol Methanol, ethanol, mixture of water or alcohol Methanol, ethanol, mixture of water or alcohol

4.

Super critical fluid extraction Microwaveassisted extraction

5.

6. 7.

Pressure liquid extraction Microwaveassisted, alkali extraction, and enzymatic hydrolysis

Temperature (°C)

Pressure (ATM)

Time Required

Based on solvent employed Only heating

NA

Depends on 100–200 cycle, 3–20 h

NA

30 min–1 h

RT

NA

3–4 days with respect to sample size Half an hour NA to 2 h 5–40 min 15–100

CO2 mixture of 35–105 CO2 and methanol Methanol; ethanol; 75–155 mixture of water and methanol; water, methanol, and alcohol Methanol 80–200 1%–2% NaOH

Volume of Solvent Required (mL)

245–450 Depends on the type of system used closed or open 10–20 bar

RT for pretreat- 1 bar ment and 50 for enzymatic saccharification

15 min to 1h 1 min for microwave

Depends on the matter, 50–100 Depends on the size of the matter

20–30 2,4,6, and 8 mL

Zygmunt and Namies´nik (2003); Huie (2002); Cunha et al. (2011); Arora et al. (2010)

a

all provide the right platform for the emergence of new global diseases. The World Health Organization has asked world nations to be ready for a postantibiotic era. Providing medicines and healthy food is a global challenge. Some medicines and nutritious food are of very high cost, like cancer drugs and nutraceuticals, and are considered as a costly commodity. In the case of food preservation, additives and preservatives are used on a very large scale in packaged food. These food additives above the ADI enhance the generation of ROS and free radical species, which when in excess cause oxidative damage to the cellular biomolecules, like DNA, proteins, and PUFA of membranes, and result in cancers, aging, asthma, ulcerative colitis, kidney stones, urinary problems, and hypertension by disturbing the metabolism of the body and disturbing the metabolic reactions. With the production of value-added products from the biomass wastes, it would be a giant step toward solving the problems related to the health-care system.

Methods for Extractions of Value-Added Nutraceuticals  49

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64  Chapter 1 Glinski, W., Glinska-Ferenz, M., Pierozynska-Dubowska, M., 1991. Neurogenic inflammation induced by capsaicin in patients with psoriasis. Acta Derm. Venereol. 71 (1), 51–54. Gupta, M., Shaw, B.P., Mukherjee, A., 2010. A new glycosidic flavonoid from Jwarhar mahakashay (antipyretic) ayurvedic preparation. Int. J. Ayurv. Res. 1, 106–111. Hänsel, R., Klaffenbach, J., 1961. Optisch aktives dihydromyricetin aus Erythrophleum africanum. Archiv. Pharm. 294 (3), 158–172. Iacobellis, N.S., Lo, C.P., Capasso, F., Senatore, F., 2005. Antibacterial activity of Cuminum cyminum L. and Carum carvi L. essential oils. J. Agr. Food Chem. 53 (1), 57–61. Ieven, M., Vlietinick, A.J., Berghe, D.V., Totte, J., Dommisse, R., Esmans, E., Alderweireldt, F., 1982. Plant antiviral agents. III. Isolation of alkaloids from Clivia miniata Regel (Amaryl-lidaceae). J. Nat. Prod. 45 (5), 564–573. Infante, R., Contador, L., Rubio, P., Aros, D., Peña-Neira, Á., 2011. Postharvest sensory and phenolic characterization of “Elegant Lady” and “Carson” peaches. Chilean J. Agr. Res. 71 (3), 445–451. Jong-Woong, A., Mi-Ja, A., Ok-Pyo, Z., Eun-Joo, K., Sueg-Geun, L., Hyung, J.K., Kubo, I., 1992. Piperidine alkaloids from Piper retrofractum fruits. Phytochemistry 31 (10), 3609–3612. Khory, R.N., Katrak, N.N., 1985. Materia Medica of India and Their Therapeutics. Neeraj Publishing House, Delhi, pp. 10-11. Lee, J.S., Lee, M.S., Oh, W.K., Sul, J.Y., 2009. Fatty acid synthase inhibition by amentoflavone induces apoptosis and antiproliferation in human breast cancer cells. Biol. Pharm. Bull. 32 (8), 1427–1432. Li, Q., He, Y.C., Xian, M., Jun, G., Xu, X., Yang, J.M., Li, L.Z., 2009. Improving enzymatic hydrolysis of wheat straw using ionic liquid 1-ethyl-3-methyl imidazolium diethyl phosphate pretreatment. Biores. Technol. 100 (14), 3570–3575. Liu, R.H., 2003. Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. Am. J. Clin. Nutr. 78 (3), 517s–520s. Mukherjee, J., Menge, M., 2000. Progress and prospects of ergot alkaloid research. Adv. Biochem. Eng. Biotechnol. 68, 1–20. Novel compound selectively kills cancer cells by blocking their response to oxidative stress. Science Daily, July 2011.Park, H.J., Kim, M.J., Ha, E., Chung, J.H., 2008. Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. Phytomedicine 15 (1), 147–151. Policegoudra, R.S., Aradhya, S.M., Singh, L., 2011. Mango ginger (Curcuma amada Roxb.): a promising spice for phyto-chemicals and biological activities. J. Biosci. 36 (4), 739–748. Pretorius, J.C., Magama, S., Zietsman, P.C., 2003. Growth inhibition of plant pathogenic bacteria and fungi by extracts from selected South African plant species. S. Afr. J. Bot. 20, 188–192. Riju, A., Sithara, K., SUJA, S.N., Shamina, A., EAPEN, S.J., 2009. In silico screening major spice phytochemicals for their novel biological activity and pharmacological fitness. J. Bioequival. Bioavail. 1 (2), 63–73. Rossi, F., Jullian, V., Pawlowiez, R., Kumar-Roiné, S., Haddad, M., Darius, H.T., Gaertner-Mazouni, N., Chinain, M., Laurent, D., 2012. Protective effect of Heliotropium foertherianum (Boraginaceae) folk remedy and its active compound, rosmarinic acid, against a Pacific ciguatoxin. J. Ethnopharmacol. 143 (1), 33–40. Shamsa, F., Monsef, H., Ghamooshi, R., Verdian-rizi, M., 2008. Spectrophotometric determination of total alkaloids in some Iranian medicinal plants. Thai J. Pharm. Sci. 32, 17–20. Talavéra, S., Felgines, C., Texier, O., Besson, C., Mazur, A., Lamaison, J.L., Rémésy, C., 2006. Bioavailability of a bilberry anthocyanin extract and its impact on plasma antioxidant capacity in rats. J. Sci. Food Agr. 86 (1), 90–97. Ulrich, S., Wolter, F., Stein, J.M., 2005. Molecular mechanisms of the chemopreventive effects of resveratrol and its analogs in carcinogenesis. Molecular nutrition & food research 49 (5), 452–461. Vila, F.C., Colombo, R., de Lira, T.O., Yariwake, J.H., 2008. HPLC microfractionation of flavones and antioxidant (radical scavenging) activity of Saccharum officinarum L. J. Braz. Chem. Soc. 19 (5), 903–908. Wasser, S.P., Weis, A.L., 1999. Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms: a modern perspective. Crit. Rev. Immun. 19 (1). Wolter, F., Ulrich, S., Stein, J., 2005. Molecular mechanisms of the chemopreventive effects of resveratrol and its analogs in colorectal cancer: key role of polyamines? J. Nutr. 134 (12), 3219–3222.

CHAPTE R 2

Modern Extraction Techniques for Drugs and Medicinal Agents Sudipta Saha*, Ashok K. Singh*, Amit K. Keshari*, Vinit Raj*, Amit Rai*, Siddhartha Maity** *Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India; **Jadavpur University, Kolkata, West Bengal, India

1 Introduction The physicochemical properties of drugs and medicinal agents derived from natural origins mostly rely on the selection of appropriate extraction techniques (Sasidharan et al., 2011). Extraction is the pioneer step of the study of any medicinal plant, playing a crucial role in the final outcomes. Extraction techniques are, therefore, occasionally referred as “sample preparation techniques” (Hennion et al., 1998). The traditional extraction techniques are time-consuming, lack efficiency in extracting the target molecule, and need large volumes of nonenvironmentally benign organic solvents, such as dichloromethane and methanol, sorbents, and sample. Traditional solid–liquid extraction (SLE) techniques consist of maceration, soxhlet extraction, percolation, soaking, turbo-extraction (high-speed mixing), and sonication. Apart from this, the current extraction techniques provide fast processing of samples, easy automation, high reproducibility, and use of low volumes of organic toxic solvents in compliance with green analytical chemistry. “Green extraction” depends on the improvement of extraction techniques that minimize energy consumption, allocate the utilization of environmentally benign solvents and inexhaustible natural products, and ensure a safe and high-quality extract (Vazquez-Roig and Picó, 2015). Furthermore, when considering the extraction of drugs and medicinal agents that are sensitive, thermolabile, and found in low concentrations, traditional extraction techniques might not be the best option, probably due to very low product yields. To acquire those drugs and medicinal agents in an environmental friendly way with adequate yields, a green extraction approach is required (Mustafa and Turner, 2011). These newer and resourceful extraction techniques, robust for the need of green analytical chemistry, are pressurized liquid extraction (PLE), microwave-assisted extraction (MAE), different types of liquidliquid microextraction (LLME), and supercritical fluid extraction (SFE) (Vazquez-Roig and Picó, 2015). Ingredients Extraction by Physicochemical Methods in Food http://dx.doi.org/10.1016/B978-0-12-811521-3.00002-8

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Copyright © 2017 Elsevier Inc. All rights reserved.

66  Chapter 2 However, between both the traditional and newer methods established to date, no single method is considered a standard for the extraction of biochemical ingredients. The assortment of extraction methods frequently rely on the critical input parameters, an understanding of the nature of the matrix embedded with the extracting compounds, the chemistry of biochemical ingredients to be extracted, and the scientific skill (Azmir et al., 2013). Until now, numerous extraction techniques and their utilization in diverse analytical fields have been increasing day by day, usually to progress compatibility with modern analytical instruments or to consent to utilize an environmental friendly way of green analytical chemistry. In this chapter, the latest developments toward modern extraction techniques will be briefly explained, and the variations in previously existing techniques for the extraction of different bioactive compounds in recent years will be described. The main aim of this chapter is to provide for the reader a brief layout to the essentials and utilization of various recently developed extraction method for the analysis of bioactive ingredient.

2  Various Extraction Procedures 2.1  Pressurized Liquid Extraction PLE combines elevated pressure and temperature with liquid solvents to attain rapid and proficient extraction of the analytes from the solid matrix. It applies maximum temperatures with a decrease in solvent viscosity, which increases the solvent’s capability to wet the matrix and solubilize the target component. Temperature also functions in the distribution of analyte–matrix bonds and inspires analyte diffusion to the matrix surface. However, PLE has significant importance over challenging techniques with regards to solvent use, time saving, automation, and efficiency. For example, PLE shows an advantage over MAE in that no extra filtration step is essential since the matrix ingredients that are not solubilize in the extraction solvent may be received within the sample extraction cell. This is very expedient for the determination of automation and on-line coupling of the separation and extraction techniques (Carabias-Martínez et al., 2005). The technique is used for extraction with solvents at a temperature and high pressure without their critical point being reached; it has received different names, such as pressurized fluid extraction (PFE), accelerated solvent extraction (ASE), pressurized-hotwater extraction (PHWE), high-pressure high-temperature solvent extraction (HPHTSE), and subcritical solvent extraction (SSE). If water is used as a solvent for the extraction, then the technique is called PHWE, subcritical water extraction, or superheated water extraction (Mustafa and Turner, 2011). More specifically, it depends on which water solvent at atmospheric pressure below the critical point of water (374°C/647 K, 22.1 MPa) and above the boiling point of water (100°C/273 K, 0.1 MPa) is used (Plaza and Turner, 2015).

Modern Extraction Techniques for Drugs and Medicinal Agents   67

Figure 2.1: The main parts of a dynamic PLE system (A) and a static PLE system (B) (Plaza and Turner, 2015).

2.1.1  Method of pressurized liquid extraction technique Here we address how to perform extraction practically using water as extractant. First, either tap or deionized water is used as the extractant. The water might be oxygen-free for avoiding oxidation of the analytes. The methods most commonly used for obtaining oxygen-free water are a helium purge or ultrasound (sonication), of which the former is more economic if an ultrasound bath is available. There are two types of equipment: dynamic (continuousflow) systems and static (batch) systems, and combinations of the two, (Fig. 2.1) (Plaza and Turner, 2015). Dynamic PLE basically needs a pump, an extraction vessel, a heating device, a pressure restrictor, and a collection vial. The pump delivers water to the extraction vessel, and via the pressure restrictor to the collection vial. The pump should be able to achieve the pressure necessary to keep the water in a liquid state during the extraction process (normally 3.5–20 MPa).

68  Chapter 2 Heating of the water is by use of an oven, heating tape, or a heating jacket. The extraction vessel is usually made of stainless steel, and should have frits at both ends in order to avoid sample losses. For a typical extraction of bioactive compounds at a moderate temperature and pressure, 100–200°C and 5–10 MPa, an empty high-performance liquid chromatography (HPLC) column may be used as an extraction vessel. However, in case the temperatures are near the critical point, above 250°C, the extraction vessel might be of a corrosion-resistant metal alloy (e.g., Hastelloy). Pressure restriction is used to control the pressure within the extraction vessel and to prevent boiling-off effects of water at the exit of the extraction vessel. In static PLE, a pump is unnecessary and convection is accomplished using a stirrer to speed up the mass transfer. The extraction vessel in static PLE is usually of wider diameter than in dynamic PLE, for fit in the stirrer. For heating, an oven, a heating jacket, or heating tape is appropriate. A pressure restrictor is not needed, unless the speed of removing the extract from the vessel is to be controlled (Plaza and Turner, 2015). There are advantages and disadvantages for using both types of system. Static PLE is simpler and easier to use than a pump and does not need pressure restrictor. The residence time of the analytes is greater than in dynamic PLE, which may cause thermally labile analytes to degrade (Liu et al., 2013a). Furthermore, in static PLE, equilibrium for distribution of analytes from the sample matrix to the extractant will stabilize after some time, since the volume of the extractant is constant. However, in dynamic PLE, the residence time of analytes in the hightemperature water is shorter, since fresh extractant is continuously being pumped into the extraction vessel and out to the collection vial. In this case, the flow rate of the extraction will control the residence time, so extraction and degradation kinetics in PLE are easier to control using a dynamic extraction setup. The disadvantage of dynamic PLE is that it is more costly, and there is always a risk of clogging inside the tubing during the extraction. Downstream of the extraction vessel, water with the extracted analytes is cooled to temperatures at which some of the extracted analytes are no longer soluble, so they precipitate and block the tubing. There are two ways to avoid this problem. One is to use heating tape around the tubing from the exit of the oven to the collection vial. Another is to use an additional pump to wash the lines after the extraction vessel and before the pressure restrictor (Monrad et al., 2012). 2.1.2  Method optimization Extraction of analytes from solid and semisolid samples can be described by the following five steps: 1. 2. 3. 4. 5.

wetting the sample matrix with solvent; to initial desorption from the sample matrix; to diffuse inside the pores of the sample matrix; to partition between the extractant and the sample matrix; to diffuse through the sluggish extractant layer until the zone of convection is reached (Pawliszyn, 2003).

Modern Extraction Techniques for Drugs and Medicinal Agents   69 All these steps happen more or less in parallel. In PHWE, the temperature is the key parameter to optimize, since it affects the efficiency of all these five steps, as described earlier. In addition, extraction time and/or flow rate are important variables to optimize. 2.1.3  Influential parameters The higher temperature of the water leads to improved wetting of the sample matrix [see preceding step (1)]. Further, increasing the temperature also favors mass-transfer kinetics by disrupting analyte-matrix interactions, especially hydrogen bonding and other dipoledipole forces, by way of promoting initial desorption of the analytes from the sample matrix [step (2)]. A higher temperature also results in faster diffusivity [steps (3) and (5)] as altered (usually higher) solubility, the latter leading to a shift in Z of the analytes between the extractant and the sample matrix [step (4)]. In summary, an elevated temperature in PHWE brings several advantages in terms of improved extraction kinetics. There are three main drawbacks in using elevated temperatures in PHWE: decreasing selectivity of the extraction, pertinent degradation of the analytes, and other chemical reactions in the sample matrix (Plaza and Turner, 2015). A sustain flow system with a high enough flow rate of the extractant minimizes chemical reactions during PLE. A higher flow rate will not only decrease the residence time for the analytes in the elevated temperature water but also enhance the extraction rate of the analytes (Liu et al., 2013a). Pressure has very little influence on the properties of water, as long as the water remains in the liquid state. Hence, a pressure of 5–10 MPa is usually employed unless the saturation pressure of water is used (Plaza and Turner, 2015). The poring of some inorganic and organic modifiers, surfactants, and additives may increase the solubility of the analytes in the extractant, and affect the physical properties of the desorption of analytes and the sample matrix from the sample. For example, 5% ethanol and 1% formic acid in water favored the extraction of anthocyanins from red cabbage (Arapitsas and Turner, 2008). The particle size of the sample influences the extraction kinetics since a smaller particle size leads to increasing contact surface between the sample and the extractant. The solventto-sample ratio is an important parameter in PHWE. An increase in the ratio of extractant to sample results in a larger fraction of the analytes being extracted without replacing the extractant with fresh solvent. The maximum of solvent to sample ratio need more water to be heated (Rezaei et al., 2013). The moisture content of the sample is another parameter that may influence the extraction yield. Some studies show that crude samples with high moisture content give better extraction yields of polyphenols than dried samples (Monrad et al., 2014).

70  Chapter 2 2.1.4 Applications During recent years, different bioactive compounds have been extracted through either static or dynamic PHWE techniques, which include polysaccharides (from Lycium barbarum, Chlorella vulgaris, Himanthalia elongate, Haematococcus pluvialis, and Dunaliella salina), phenolic compounds (from lemon balm, grape pomace, and potato peel), antioxidants (cow cockle seed, oregano, and olive leaves), flavonols (apple by-products, grape pomace, and Moringa oleifera leaf), and anthocyanins (red cabbage, red onion, and grape pomace) (Plaza and Turner, 2015).

2.2  Microwave-Assisted Extraction MAE has drawn significant research attention in various fields for medicinal plant research, moderate capital cost, special heating mechanism, and its good efficacy under atmospheric conditions. Microwaves consist of an electric field and a magnetic field oscillating at frequency ranged from 0.3 to 300 GHz. Microwaves may enter into calm materials and interact with the polar components to generate heat. The principle of MAE depends on ionic conduction and dipole rotation via a direct effect of microwaves on molecules of the extracted system and also works because only targeted and selective materials may be heated on the basis of their dielectric constant (Sparr Eskilsson and Björklund, 2000). The heating process and efficiency of the microwave are based on dissipation factor of the material tan δ. However, the measurement of the sample to absorb microwave energy and disperse heat to the neighboring molecules is given by Eq. (2.1). tan δ = ε ′′ / ε ′ (2.1) where ε″ is the dielectric loss that expresses the efficiency of changing microwave energy into heat energy, whereas ε′ is the dielectric constant, denoting the measurement of the ability of the material to absorb microwave energy. The rate of conversion of electrical energy into thermal energy in the material is described by Eq. (2.2). P = K ⋅ f ε ′E 2 tan δ (2.2) where P indicates the microwave power dissipation per unit volume, f is the applied frequency, K is a constant, E is the electric field strength, ε′ is the material’s absolute dielectric constant, and tan δ is the dielectric loss tangent (Chan et al., 2011). MAE may happen in any one or several of the following three heating mechanisms: 1. Extracting analyte into a single solvent or mixture of solvents that absorb microwave energy strongly. 2. Extracting analyte into a combined solvent containing both high and low dielectric losses mixed in various proportions. 3. Extracting analyte with a microwave transparent solvent from a sample of high dielectric loss. MAE can be carried out in a closed or open microwave transparent vessels; thereby sample and solvent are placed and then exposed to microwave energy (Madej, 2009).

Modern Extraction Techniques for Drugs and Medicinal Agents   71

Figure 2.2: (A) Closed type microwave system and (B) open type microwave system (Chan et al., 2011).

2.2.1  Method of microwave-assisted extraction technique MAE may be classified into “closed system” and “open system” on the basis of operating above and under atmospheric pressure, respectively. Further, consider the closed system and open system, for which schematic diagrams are shown in Fig. 2.2 (Chan et al., 2011). In a closed MAE system, the different mode of microwave radiation is used for extraction in a sealed vessel with sustained microwave heating. High working temperature and pressure of the system permit fast and competent extraction. The pressure is essentially controlled inside the extraction vessel in such a way that it cannot go beyond the working temperature and pressure of the vessel and can be regulated above the normal boiling point of the extraction solvent. Recent upgrading of the closed system has led to the improvement of high-pressure microwaveassisted extraction (HPMAE). The increase in pressure and temperature expedite microwaveassisted extraction due to the capability of extraction solvent to absorb microwave energy. The closed system makes fast and proficient extraction with less solvent spending, easily preventing the loss of volatile compounds with limited sample throughput (Wang et al., 2008). The thermolabile compounds are safely extracted out using an open system to counter the shortcomings of a closed system. The productivity of extraction has greater volumes of solvent that might be used any time during the process. Basically, the open system operates at more mild conditions. The open MAE system is frequently used in the extraction of active compounds and also used in analytical chemistry. This system transports at atmospheric conditions and only part of the vessel is directly uncovered to the promulgation of microwave radiation (monomode). The condensation of any vaporized solvent that happens via the upper part of the vessel is connected to a reflux. Besides that, multimode radiation may also be engaged in an open MAE system with the reflux unit (Luque-García and Luque de Castro, 2003).

72  Chapter 2 Poor extraction yield due to oxidation and thermal degradation of some active compounds has led to the enlargement of more proficient MAE that requires additional instruments on top of the commercial system. These are vacuum microwave-assisted extraction (VMAE), nitrogenprotected microwave-assisted extraction (NPMAE), dynamic microwave-assisted extraction (DMAE), ultrasonic microwave-assisted extraction (UMAE), and solvent-free microwaveassisted extraction (SFME). In the cases of NPMAE and VMAE, additional vacuum pump and nitrogen sources are supplemented. The vacuum pump is used to grant vacuum pressure for VMAE and it is also used to remove oxygen before nitrogen is pressurized into the vessel for NPMAE. Further, a reflux system is installed to avoid any additional pressure built up during the extraction process. In some NPMAE, the inert gas is pressurized straight inside the extraction vessel containing the sample–solvent mixture—and put into the closed-type microwave cavity. For UMAE, the ultrasonic sound transducer might be installed so that the wave can proliferate directly into the extraction vessel of the alert-type microwave system. Further, in the case of DMAE, most of the instrument setup is custom made. The system made up MAE extraction and HPLC analysis in a single step. The extraction step begins by introduction of the sample vessel into the resonance cavity and the solvent is circulated through the extraction loop. The heating of the microwave is activated once the solvent flow rate reaches steady state. The regulation screws in the microwave resonance are attuned to decrease the reflected power. When the extraction is complete, the extract is determined by the sample loop. The solvent is then mixed with the mobile phase and proceeds to the analytical step (Chan et al., 2011). Apart from these, the SFME method involves insertion of vegetable material in a microwave reactor without the addition of any solvent or water. The inside heating of the in situ water within the plant material distends the plant cells and leads to breakdown of the cells. Thus, this process releases essential oils containing bioactive compounds, which are evaporated by the in situ water of the plant material. The continuous condensation of the distillate outside the microwave oven allows the cooling of the system, which comprises essential oils and water. The extreme water is refluxed to the reactor to maintain the proper humidity rate of the plant materials (Li et al., 2013). 2.2.2  Influential parameters The main parameters influencing MAE performance, include solvent nature, the solvent-tofeed ratio, microwave power, extraction time, and temperature. In the extraction of most bioactive compounds, organic solvents are used. When selecting the solvent, consideration should mainly be focused on the microwave-absorbing properties of the solvent, selectivity toward the analyte, and interaction of the solvent with the matrix. Generally, in conservative extractions, a maximum volume of solvent has augmented the revival of the analyte, but, in MAE, the same move toward may give lower recoveries, which

Modern Extraction Techniques for Drugs and Medicinal Agents   73 may be due to the inadequate stirring of the solvent by the microwaves. The solvent volume depends on the type and the size of the sample, but, on average, the amounts of solvent may be about 10 times less than those used in classical extractions. The microwave power and the corresponding time depend on the type of sample and solvent used. In theory, one should use high-power microwaves to reduce exposure time as much as possible. However, in some cases, a very high-power microwave decreases the extraction efficiency (EE) by degrading the sample or rapidly boiling the solvent in open-vessel systems, which hinders contact with the sample. Generally, extraction times in MAE are much shorter than those of classical extraction techniques. Usually, elevating extraction times above the optimal range does not improve EE, and, in some cases, may even decrease analyte recoveries (e.g., thermolabile compounds). In most cases of the MAE, high temperatures result in enhanced EE, but particular deliberation should be specified to applications dealing with thermolabile substances, which may be decomposed at high temperatures. Further, by introducing inspiring in MAE, the negative effect of low solvent-to-feed ratio of extraction yield may be reduced (Madej, 2009). 2.2.3 Applications Standard MAE is commonly employed either in open or closed systems to extract thermostable compounds. For extraction of degradable active compounds, there are various modified MAE techniques that are suitable for the application. DMAE is suitable to extract degradable compounds that require multiple extraction cycles as the technique performs under mild conditions and in a continuous manner. This technique promotes efficient and fast analytical step, as it may be coupled on-line with HPLC analysis system. Moreover, for highly brittle compounds, which forecast high risks of oxidation and thermal degradation, VMAE is appropriate because the extraction is done at low temperature and in a vacuum condition. Alternatively, extraction of thermally degradable compounds can also be achieved by NPMAE. It gives faster extraction than VMAE but requires additional extraction steps. Besides, SFME is preferable to for use in essential-oil extraction and it is more efficient than the traditional HD method. In some circumstances in which the associated active compounds have low diffusion and are difficult to extract, UMAE can be employed because it improves the mass-transfer mechanism and reduces the extraction time. This technique can provide high activation energy or the impact energy required for the extraction to proceed (Chan et al., 2011).

2.3  Supercritical Fluid Extraction SFE is the process of extraction using supercritical fluids as the extracting solvent. Extraction is usually from a solid matrix, but can also be from liquids. SFE provides several operational advantages since it uses supercritical solvents, with different physicochemical properties, such as density, diffusivity, viscosity, and dielectric constant. The extraction speed is mainly

74  Chapter 2 dependent on the viscosity and diffusivity of the mobile phase. With a low viscosity and high diffusivity, the component that is to be extracted can pass through the mobile phase easily. The lower viscosity and higher diffusivity of supercritical fluids, as compared to regular extraction liquids, help the components to be extracted faster than through other techniques. Thus, an extraction method may take just 10–60 min with SFE, whereas it would take hours or even days with classical methods. Altering its pressure and/or temperature can modify the density of the supercritical fluid. Since density is related to solubility, by varying the extraction pressure, the solvent strength of the fluid can be adapted. Other advantages, compared to other extraction techniques, are the use of solvents generally known as safe (GRAS) and the higher efficiency of the extraction process in terms of lower extraction times and increasing yields (da Silva et al., 2016). 2.3.1  Fluid materials used in supercritical fluid extraction There are several material compounds that may be used as supercritical fluids; the one most frequently used is carbon dioxide as a solvent. For practice, more than 90% of all analytical SFE is carried out with carbon dioxide (CO2) for numerous practical reasons. Besides having a relatively low temperature (32°C) and critical pressure (74 bar), CO2 is comparative, nonflammable, nontoxic, existing in high purity at rather a low cost, and is easily removed from the extract. In the supercritical state, the CO2 shows similar polarity with liquid pentane and is, therefore, superlatively suitable for lipophilic compounds. The major disadvantage of CO2 is its lack of polarity for the extraction of polar analytes. In the 1990s, a number of reports were published about the alternative of N2O as an extraction fluid for analytical SFE. This fluid was measured to be more suitable for polar compounds because of its enduring dipole moment. One of the applications in which N2O exhibited major progression when compared to CO2 is, for example, the extraction of polychlorinated dibenzodioxins from fly ash. Unfortunately, this fluid has been shown to cause violent explosions when used for samples having high organic content and should, therefore, be used only when absolutely necessary. Other more exotic supercritical fluids that have been used for environmental SFE are freons and SF6. The SF6 is a nonpolar molecule (although easily polarizable) and as a supercritical fluid, it has been revealed to selectively extract aliphatic hydrocarbons up to around C-24 from a mixture containing both aliphatic and aromatic hydrocarbons. Freons, particularly CHClF2 (Freon-22), have on a number of occasions been shown to augment the EE compared to conducting extractions with CO2 (Pourmortazavi and Hajimirsadeghi, 2007). Although supercritical H2O has often been used for the obliteration of hazardous organics, the high pressure and temperature needed (P > 221 bars and T > 374°C) in concert with the corrosive nature of H2O in these circumstances, has limited the promising practical applications in plant-oil analysis. H2O at subcritical conditions is used as an effective fluid for the extraction of several classes of essential oil. Propane, ethane, dimethyl ether, ethylene, and so forth have also been suggested as solvents under sub- and supercritical circumstances

Modern Extraction Techniques for Drugs and Medicinal Agents   75 for extraction (Illés et al., 1997). A substitute to CO2 in supercritical extractions is the exploit of propane. Although propane does not recommend many of the characters that are generally associated with CO2, this reasonably inexpensive solvent can be a better choice for the extraction of oils and natural products. Propane does not leave a toxic filtrate just as CO2 but the required extraction pressures are inferior to those applied with CO2 (Sparks et al., 2006). 2.3.2  Method of supercritical fluid extraction techniques Only dry samples might be preferred for the extraction through SFE. When a fresh plant material is extracted, its high moisture content may cause mechanical difficulties, such as restrictor clogging due to ice formation. One uncomplicated yet efficient way to avoid such problems is to mix the sample with anhydrous Na2SO4. Anhydrous Na2SO4 can improve SFE results because: (1) it can make available improved contact between SFs and samples, (2) it can decrease the dead volume effects, and (3) it can effectively retain the moisture. Further researchers, however, assumed that silica gel was a better choice in retaining the moisture for SFE of fresh samples. Enhanced SFE results were also experiential as fresh ginger samples were blended with coarse granulated celite (30–60 mesh) before loading the samples into the SFE cell for extraction. Sample particle size is a critical factor for a suitable SFE process. Large particles may result in lengthened extraction because the process can become diffusion controlled. Therefore, pulverizing a sample into fine powder can speed up the extraction and progress the efficiency, but it may also introduce complexity in maintaining an appropriate flow rate. One effective way to prevail over the flow rate difficulty is to pack the sample with glass beads or other rigid inert materials, such as sea sand (Lang and Wai, 2001). The required apparatus for a basic SFE setup is simple. Fig. 2.3 depicts the basic elements of an SFE instrument, a pressure tuning injection unit, composed of a reservoir of supercritical fluid, two pumps (to take the components in the mobile phase in and to throw them out of

Figure 2.3: Scheme of an Idealized Supercritical Fluid-Extraction Instrument (Sánchez-Camargo et al., 2014; Cavalcanti and Meireles, 2012).

76  Chapter 2 the extraction cell), and a collection chamber. There are two principle modes to run the instrument: static extraction and dynamic extraction. In the dynamic extraction, the second pump transfers the materials out to the collection chamber and is always open during the extraction process. However, the mobile phase reaches the extraction cell and extracts components to take them out consistently. In the static extraction experiment, there are two different steps in the process: 1. The mobile phase fills the extraction cell and interacts with the sample. 2. The second pump is opened and the extracted substances are taken out at once. In order to choose the mobile phase for SFE, parameters taken into consideration, include the polarity and solubility of the samples in the mobile phase. Carbon dioxide is the most common mobile phase for SFE. It has the capability to dissolve nonpolar materials, such as alkanes. For semipolar compounds (such as polycyclic aromatic hydrocarbons, aldehydes, esters, alcohols, etc.) carbon dioxide can be used as a single-component mobile phase. However, for compounds that have polar characteristic, supercritical carbon dioxide must be modified by the addition of polar solvents, such as methanol. These extra solvents can be introduced into the system through a separate injection pump. There are two modes in terms of collecting and detecting the components: off-line and on-line extraction. Off-line extraction occurs by captivating the mobile phase out with the extracted components and directing them into the collection chamber. At this point, the supercritical fluid phase is evaporated and free to the atmosphere and the components are captured in a convenient adsorption surface or a solution. Then the extracted fragments are processed and prepared for a separation method. This extra manipulation step between extractor and chromatography instrument can cause errors. In the on-line method, all extracted materials are directly transferred to a separation unit due to a more sensitive, usually a chromatography instrument, without taking them out of the mobile phase. In this extraction/detection type, there is no extra sample preparation after extraction for the separation process. This minimizes the errors coming from manipulation steps. Additionally, sample loss does not occur and sensitivity increases (Cavalcanti and Meireles, 2012; Sánchez-Camargo et al., 2014). 2.3.3  Influential parameters For successful SFE, a number of factors must be in use on reflection prior to the experiments. These factors, include the type of sample, type of fluid; method of sample preparation; choice of modifiers; method of fluid feeding; and extraction conditions including temperature, pressure, flow rate, and extraction time. To optimize the SFE conditions, a statistical experimental design based on a “second order central composite design” was carried and reported by Adas¸og˘lu et al. (1994). The diffusion rate of a compound from the sample matrix may be exaggerated by the following three factors: (1) occupation of the matrix

Modern Extraction Techniques for Drugs and Medicinal Agents   77 sites by the SF molecules, which could decrease the affinity of the matrix for the solutes; (2) dissolution of the solutes in the SF, which is directly related to the fluid density; and (3) temperature effects, which can influence the volatility of the solutes, particularly for those with high boiling points. Apart from this, the solubility of a target compound in an SF is a major factor determining its EE. The solubility is controlled by the sum of two factors: the volatility of the substance, which is a function of temperature; and the salvation effect of the SFs, which is a function of fluid density [8]. To achieve a good selectivity for an SFE process, careful control of the fluid density is essential. By controlling the fluid density, fractionation of the extracts could be achieved (Lang and Wai, 2001). 2.3.4 Applications SFE can be applied to a broad range of materials, such as carbohydrates, polymers, oils, lipids, pesticides, organic pollutants, volatile toxins, polyaromatic hydrocarbons, biomolecules, foods, flavors, explosives, pharmaceutical metabolites, and organometallics, and so forth. Common industrial applications consist of the biochemical industry and pharmaceutical; industrial synthesis in the polymer industry; and extraction, natural product chemistry, and the food industry. Examples of materials analyzed in environmental applications: oils and fats, pesticides, alkanes, organic pollutants, volatile toxins, herbicides, nicotine, phenanthrene, aromatic surfactants, fatty acids, in samples from clay to petroleum waste, from soil to river sediments. In food analyses: caffeine, peroxides, oils, acids, cholesterol, and so forth are extracted from samples, such as coffee, olive oil, lemon, cereals, wheat, potatoes, and dog feed. Through industrial applications, the extracted materials vary from additives to different oligomers, and from petroleum fractions to stabilizers. Samples analyzed are plastics, PVC, paper, wood, and so forth. Drug metabolites, enzymes, and steroids are extracted from plasma, urine, serum, or animal tissues in biochemical applications (Herrero et al., 2010).

2.4  Liquid Phase Microextraction Liquid-liquid extraction (LLE) is a process to transfer the analyte from an aqueous sample to a large amount of water-immiscible solvent based on their relative solubilities. LLE is almost certainly the oldest separation technique in analytical chemistry and residue between the best-known and commonly used techniques. Although LLE offers many advantages, it has been overshadowed by the extensive use of solid-phase extraction (SPE). The most significant merits of both SPE, which have made them so popular among analytical chemists, mainly include: (1) the efficient use of time and labor; (2) the significant reduction in a number of organic solvents used, thus leading to the lower cost for analysis; (3) the reduction in the amount of waste generated, which contributes to their environmentally safe character; and (4) the possibility of their being automated (Andruch et al., 2012). However, to minimize the

78  Chapter 2 known disadvantages of LLE while also preserving the advantages it offers, a great variety of miniaturized pretreatment techniques based on LLE have been developed, termed as liquid phase microextraction (LPME)/solvent microextraction. LPME emerged from liquid-liquid extraction; it is a widely used sample extraction and separation procedure in spite of its clear disadvantages, such as high consumption of time and strong toxicity of solvent, as well as its tedious application (Asensio-Ramos et al., 2011). LPME, in general, takes place between a number of microliters of water-immiscible solvent extraction phase or acceptor phase (AP) and an aqueous sample phase or donor phase (DP), which contains the target analytes of interest. LPME can be classified into three main categories: single-drop liquid-phase microextraction (SD–LPME), dispersive liquid-liquid microextraction (DLLME), and hollow fiber liquid-phase microextraction (HF–LPME) (Yan et al., 2014). 2.4.1  Single-drop liquid-phase microextraction Single-drop microextraction (SDME), as first advanced by Frederick F. Cantwell in the late 1990s, was in the beginning shared with gas chromatography. Presently, seven dissimilar modes of solvent microextraction fall under the category of SDME. However, the headspace (HS) and direct immersion (DI) modes are the ones that are used repeatedly. A microliter drop of water-immiscible organic solvent is either in the HS above the sample or immersed directly into the sample by an ordinary chromatography syringe. The aqueous sample is stirred and after the extraction, the drop is retracted back into the syringe and transferred into the chromatography system for detection. Despite the information that the favored technique for the analysis of extracts after SDME is gas chromatography, to date SDME has also been collective with high-performance liquid chromatography, graphite furnace atomic absorption spectrometry, inductively coupled plasma mass spectrometry, capillary electrophoresis, and mass spectrometry (Andruch et al., 2012). To decrease evaporation risk during the process to obtain the desired results and extraction period, a number of significant factors of extraction solvent, such as relatively low vapor pressure or high boiling point, density, suitable chromatographic behavior, high viscosity, and high EE or EF for the target analytes must be considered (Bai et al., 2008). On the basis of these facts, frequent extraction solvents used are toluene, hexane, octane, dodecane, and xylene. Except that, certain ionic liquids (ILs), such as 1-butyl-3-methylimidazollium hexafluorophosphate ([BMIM][PF6]), 1-hexyl-3-methylimidazolium hexafluorophosphate ([HMIM][PF6]), and 1-octyl-3-methylimidazolium hexafluorophosphate ([OMIM][PF6]) can also provide satisfactory results with better reproducibility. This production is due to the ILs, with surface tension and high viscosity, which helps to form a stable drop of a very much larger volume to prolong the extraction time. In addition, β-cyclodextrine, surfactants, and supramolecular solvents as extractants were also planned in the field of SD-LPME (Yan et al., 2014).

Modern Extraction Techniques for Drugs and Medicinal Agents   79 In short, SD-LPME has to be converted into one of the most popular sample preparation techniques because of its: (1) simplicity and speed, (2) low cost and low environmental pollution, (3) extensive range of solvent types being selected and used, (4) applicability to different complex matrices, (5) extraction and separation of both inorganic and organic compounds, and (6) compatibility with chromatographic or electrophoretic injection systems. However, HS-SDME is more often applied to analytes with relatively high vapor pressure, such as the volatile components of essential oil (Deng et al., 2005). 2.4.2  Dispersive liquid-phase microextraction Dispersive liquid-liquid microextraction is a miniaturized version of conventional LLE and requires only microliter volumes of solvents. As the name suggests, DLLME is equivalent to a miniaturized type of LLE that is generally established on a ternary component solvent system, in which an appropriate disperser solvent is introduced to help the dispersion of an organic extraction solvent into an aqueous sample and further achieve a highly efficient extraction. Briefly, a DLLME procedure may be outlined as follows: (1) the injection of extraction and disperser solvents into sample solution, (2) the formation of so-called cloudy state due to the solvency of the disperser solvent with two other solvents, (3) the achievement of extraction equilibrium in a short time based on the extensive surface contact between the droplets of the extraction solvent and the sample, and (4) centrifugation to completely separate the two phases and force the organic phase with the extracted analyte to the bottom (Yan and Wang, 2013). The mixture of dispersive solvent and extraction solvent is rapidly injected into a sample solution with a glass syringe. At the moment of injection, fine droplets of the extraction solvent are dispersed in the aqueous phase, forming a so-called cloudy state, which should remain stable for a while. In this regard, the very small size of the extraction droplets, the big surface area thus produced enables a very rapid mass transfer of the analyte from one phase into another. The cloudy solution is then uncovered to centrifugation to completely separate the two phases and force the organic phase with the extracted analyte to the bottom of the test tube (Andruch et al., 2012). Obviously, the advantages of DLLME are mainly the following: (1) the use of only microliter volumes of extraction solvent, which makes the procedure environmentally friendly, (2) the short extraction time as a result of the rapid achieving of the equilibrium state, and (3) the high enrichment factor as a result of the high phase ratio. Accordingly, the DLLME technique is simple, quick, efficient, and simultaneously meets the development requirement of green chemistry. Nevertheless, this technique has certain limitations, which primarily result from requirements related to the extraction and disperser solvents—namely: (1) the extraction solvent has to be immiscible with water, have a high extraction potential for the target analyte, and has to have

80  Chapter 2 a density higher than that of water due to simple phases separation by centrifugation; (2) the disperser solvent, on the other hand, has to be miscible with both the extraction solvent and water (the sample solution) to enable the dispersion of fine particles of the extraction solvent into the aqueous phase containing the analyte. For this explanation, chloroform, 1,2-dichlorobenzene, carbon tetrachloride, and dichloromethane are most frequently apply as an extraction solvent, and ethanol, methanol, acetonitrile, and acetone are usually used as disperser solvent (Yan and Wang, 2013). The DLLME technique uses somewhat bigger volumes of organic solvents than are general in SDME, but this still only involves microliters. Therefore, DLLME, much like SDME, is also most often combined with GC, HPLC, GF-AAS, and FAAS detection. However, articles in which DLLME is collective with UV–vis spectrophotometry—are being published less often (Andruch et al., 2012). Furthermore, ILs, known as “green solvents,” are a group of nonmolecular solvents that can be defined as organic salts that remain in a liquid state at room temperature (RTILs). These solvents have numerous exclusive physicochemical properties, such as variable viscosity, negligible vapor pressure, and high thermal stability. On the basis of the diverse combinations of organic cations and various anions, ILs can be structurally tailored to be hydrophilic or hydrophobic, such as miscible or immiscible with the disperser solvent in DLLME. In addition, the high density and the low volatility of ILs are also significant features; the former facilitates phase separation, and the latter offers stable droplets. ILs are consequently regarded as environmentally kind replacements for traditional toxic organic solvents and can be potentially used in DLLME (termed as IL-DLLME) (Table 2.1). In the years that followed, many applications based on ILDLLME technique were carried, focusing on the determination of pesticides, metal ions, pharmaceuticals and other organic pollutants in water, food, urine, or even cosmetics (Yan and Wang, 2013). 2.4.3  Hollow-fiber liquid-phase microextraction To augment single-drop stability and decrease AP pollution from the substrate in DP or impurities, mentioned earlier, SD-LPME, hollow-fiber liquid-phase microextraction (HF-LPME) was introduced. HF-LPME is a technique that allows extraction and preconcentration of analytes from complex samples in both a simple and inexpensive way (Pedersen-Bjergaard and Rasmussen, 1999). In the two-phase LPME sampling mode (HF-LPME), the analyte is extracted from an aqueous sample to a water-immiscible extractant immobilized in the pores of a hollow fiber, typically made of polypropylene and supported by a microsyringe. In this sampling mode, the AP is organic—that is, attuned with atomic detectors for total resolve, such as HPLC and GC for the coupling of chromatographic separation techniques to atomic detectors (Psillakis and Kalogerakis, 2003).

Modern Extraction Techniques for Drugs and Medicinal Agents   81 Table 2.1: Applications of SD-LPME and ionic liquid D-LPME for the extraction of drugs. Analyte

Matrix

Salinomycin, gramicidin D Water/human urine and plasma Berberine, palmatine, Human urine tetrahydropalmatine Gatifloxacin, Human urine lomefloxacin, enoxacin, ciprofloxacin, ofloxacin, pefloxacin Mizolastine, Human urine chlorpheniramine, pheniramine Illicit drugs Horse urine Statins Serum sample/ water Growth hormones Bovine urine Sufentanil alfentanil Human urine, wastewater Amitriptyline, nortriptyline Human urine and plasma Nortriptyline, Human urine imipramine, trimeprazine, promethazine, imino dibenzyl Clozapine, desmethyl Human urine and clozapine, or clozapine serum Ephedrine, ketamine Human urine Rifaximin

Rat serum

Eprosartan, valsartan, irbesartan, losartan, telmisartan Balofloxacin

Rat serum

Emodin, metabolites

Rat urine

Rat serum

LPME Type

Detection Techniques

References

SD-LPME

MALDI-MS

Wu et al. (2011)

SD-LPME

MECK

Gao et al. (2011a)

SD-LPME

CE

Gao et al. (2011b)

SD-LPME

MECK

Gao et al. (2012)

SD-LPME SD-LPME

GC-ECD CEC

Stege et al. (2011) Jahan et al. (2015)

SD-LPME SD-LPME

GC-MS GC-FID

George et al. (2015) Fakhari et al. (2011)

SD-LPME

GC-FID

Yazdi et al. (2008)

SD-LPME

CE

Wu et al. (2014)

IL-D-LPME, [EMIM] [NtfO2] IL-D-LPME, [BMIM] [PF6] IL-D-LPME, [BMIM] [PF6] IL-D-LPME, [BMIM] [PF6]

CE

Breadmore (2011)

CE

Liu et al. (2013b)

HPLC-UV

Nageswara Rao et al. (2012) He et al. (2009)

HPLC-UV

IL-D-LPME, [BMIM] HPLC-UV [PF6] IL-D-LPME, HPLC-UV [C6MIM][PF6]

Rao et al. (2014) Tian et al. (2012)

In HF-LPME, limited to analytes with ionizable functionalities, the analyte is extracted from an aqueous sample through the water-immiscible extractant immobilized in the pores of the hollow fiber and ultimately into an aqueous phase inside the lumen of the hollow fiber. Because the AP is aqueous in this microextraction mode, the technique might be attuned not only with atomic detectors for determination of totals but also with hyphenated techniques involving HPLC separations for speciation (Pena-Pereira et al., 2009).

82  Chapter 2 Table 2.2: Comparison of advantages and drawbacks of SDME, HFME, and DLLME microextraction techniques. SDME

HFME

DLLME

Inexpensive, simple, easy to operate, nearly solvent free, more suitable for volatile and semivolatile analytes, environmental friendly, various extraction modes, ease of automation, high extraction efficiency

Inexpensive, simple, environmental friendly, high versatility and selectivity, headspace and immersion modes

Simple, high enrichment factors, rapid, inexpensive, environmental friendly, enormous contact area between acceptor phase and sample, fast reaction kinetics, instantaneous extraction, complete analyte recovery, DLLME can be coupled with SPE, SFE, SBSE, nano techniques Minor restrictions in solvent selection and automation

Problem of drop dislodgment, time- Poor reproducibility, timeconsuming, incomplete equilibrium consuming, formation of air bubble

DLLME, Dispersive liquid-liquid microextraction; SDME, single-drop microextraction; SFE, supercritical fluid extraction; SBSE, stir-bar sorptive extraction; SPE, solid-phase extraction.

Solvent impregnation of the fiber is necessary since extraction occurs on the surface of the immobilized solvent. The pores of a porous hydrophobic polymer membrane are packed with an organic liquid, which is apprehended by capillary forces. The extractant should have a polarity matching that of the hollow fiber to be easily immobilized within its pores. Usually, the extraction effectiveness gained with HF-LPME is greater than with direct-SDME, since hydrophobic hollow fibers permit the use of vigorous stirring rates to increase speed of the extraction kinetics. Moreover, the contact area between the aqueous sample and the extractant phase is higher than in the case of SDME, favoring the mass transfer rate. The use of the hollow fiber provides protection of the extractant phase and hence, the analysis of dirty samples is feasible. Moreover, the small pore size allows microfiltration of the sample, thus yielding very clean extracts (Table 2.2) (Rasmussen and Pedersen-Bjergaard, 2004).

2.5  Solid Phase Extraction SPE is a sample extraction technique normally used in laboratories for the extraction of a complex matrix, such as urine, blood, food samples, water, etc. Traditionally, liquid-liquid extraction (LLE) was developed and employed to screen for general unknowns. However, SPE is becoming more popular than LLE for analyte preconcentration and matrix removal, due to its simplicity and economy in terms of time and solvent (Picó et al., 2007). SPE has gained wide acceptance because of the inherent disadvantages of LLE, whose drawbacks include (Płotka-Wasylka et al., 2015): 1. incapability to extract polar compounds, 2. being laborious and time-consuming, 3. expense, 4. tendency to form emulsions,

Modern Extraction Techniques for Drugs and Medicinal Agents   83 5. need for evaporation of huge volumes of solvents, 6. discarding of toxic or flammable chemicals. By contrast, SPE is a more efficient separation process than LLE and is becoming one of the most routinely used procedures for the separation and preconcentration of a variety of compounds and elements from complex samples due to their well-known advantages, which include the high enrichment factor, easier to obtain a higher recovery of the analyte by using a reduced volume of solvents and the possibility of automation (off- or on-line) of the whole process. Moreover, modern regulations pertaining to the use of organic solvents have made LLE techniques undesirable. LLE procedures that need a number of consecutive extractions to make progress greater than 99% of the analyte can often be replaced by SPE methods. Furthermore, SPE does not need the phase separation required for LLE, and that eliminates errors associated with a variable or inaccurately measured extract volumes. In recent decades, the use of SPE has increased due to the progress of a variety of new materials that may be engaged as solid sorbents (Płotka-Wasylka et al., 2015). 2.5.1  Method of solid-phase extraction technique SPE is widely accepted for analyte extraction and preconcentration as a substitute to time consuming and laborious liquid–liquid extraction (LLE) procedures. SPE uses the distinction of attraction between an analyte and interferents present in a liquid matrix, for a solid phase (sorbent). This affinity allows the partition of the target analyte from the interferents. There are four steps involved in solid phase extraction (Fig. 2.4): 1. First, the cartridge is conditioned or equilibrated with a solvent to wet the sorbent. 2. The loading solution containing the analyte is percolated through the solid phase. Ideally, the analyte and some impurities are retained on the sorbent.

Figure 2.4: The Fundamental Method of SPE Technique (Herrero-Latorre et al., 2015).

84  Chapter 2 3. The sorbent is then washed to eradicate impurities. 4. The analyte is collected during this elution step. However, this technique suffers from some drawbacks, depending on the type of SPE applied, the sorbent used, and the characteristics of the sample. The most frequently used techniques make use of column immobilized SPE and these may result in long treatment times, high back-pressure in the packing method and low extraction efficiencies in convinced cases when compared to other SPE methodologies. Therefore, in the past few years, other SPE approaches, such as solid-phase microextraction (SPME), dispersive solid-phase extraction (DSPE), magnetic solid-phase extraction (MSPE), molecularly imprinted solid-phase extraction (MISPE), and matrix solid-phase dispersion extraction (MSPDE), have been applied in an effort to overcome these problems (Herrero-Latorre et al., 2015).

2.6  Carbon Nanotubes Solid Phase Extraction Nanotechnology is currently one of the largest significant trends in science, which includes the production of novel and revolutionary materials of the size of 100 nm or even smaller. Carbon nanotubes (CNTs) are part of these novel materials. Their discovery was a direct consequence of the synthesis of fullerenes, especially the buckminsterfullerene, C60. CNTs are molecularscale tubes of graphitic carbon that can be consequently considered as a graphene sheet in the shape of a cylinder (Gouda, 2014). CNTs can be visualized as sheets of graphite rolled into a tube; they are known to have strong interactions with molecules or ions. Their great surface areas show them to have potential to be used for solid-sorbent for preconcentration procedures. CNTs can be further divided into multiwalled carbon nanotubes (MWCNTs) and single-walled carbon nanotubes (SWCNTs) according to the carbon atom layers in the wall of the nanotubes. Multiwalled CNTs (MWCNTs) better reflect their structure. The key predicament when applying SPE always remains the method development and the choice of the most appropriate sorbent, which depends on the physicochemical properties of the analytes. In this sense, CNT’s high surface area; ability to establish π–π interactions; excellent chemical, mechanical and thermal stability; and so forth make them very attractive as SPE materials for either nonpolar (in the case of nonfunctionalized CNTs) and polar compounds for which functionalization of the tubes plays a key role in selectivity. Because of its elevated extraction effectiveness, the ease of method development, the lower amount of organic solvents used, and the possibilities of automation, SPE has been increasingly used regarding the extraction of various organic analytes (pesticides, pharmaceuticals, phthalate esters, and phenolic compounds), as well as inorganic analytes (Table 2.3) (Ravelo-Pérez et al., 2010).

2.7  Magnetic Solid-Phase Extraction Magnetic separation and preconcentration using magnetic carbon nanotubes (M-CNTs) give optimum and discriminating sample pretreatment measures that minimized the mandatory

Modern Extraction Techniques for Drugs and Medicinal Agents   85 Table 2.3: Applications of CNTs as SPE sorbents for the extraction of drugs. Analyte

Matrix

Detection Techniques

CNTs Characteristics

Remarks

References

Atrazine simazine

Water

GC/MS

MWCNTs

—

Benzodiazepine residues: diazepam, estazolam, alprazolam, and triazolam

Pork

GC–MS

MWCNTs

Katsumata et al. (2010) Wang et al. (2006)

Sulfonamides: sulfadiazine, Eggs and sulfamerazine, pork sulfadimidine, sulfathiazole, sulfamoxole, sulfamethizole, sulfamethoxypyridazine, sulfachlorpyridazine, sulfadoxine, and sulfisoxazole NSAIDs: tolmetin, Urine ketoprofen, and indomethacin

HPLC-UV

MWCNTs

Analytes were extracted by ultrasonic-assisted extraction Ultrasonic-asFang et al. sisted extraction (2006) and online SPE

CE-MS

Barbiturates: barbital, amobarbital, and phenobarbital

Pork

GC–MS/MS

Carboxylated SWCNTs immobilized on an inert porous glass MWCNTs

Tetracyclines: oxytetracycline, tetracycline, and doxycycline Cephalon, cephalexin, cephradine, benzoic acid, cefaclor, sulfathiazole, sulfadiazine, sulfamethazine, phenol, hydroxyquinone, guaiacol, 1,3,5-trihydroxybenzene, and 3,5-dihydroxybenzoic acid Antidepressants: imipramine, nortriptyline, desipramine, amitryptiline, clomipramine, trimipramine, trazodone, fluoxetine, and mianserin

Surface water

CE-MS

SWCNTs

Tap and well water

HPLC-UV

MWCNTs

Urine

HPLC-UV

MWCNTs

—

Suárez et al. (2007b)

Barbiturates were extracted by ultrasonicassisted extraction and derivatized after SPE procedure Only MWCNTs provided adequate results Retention abilities of C18 and graphitized carbon black were also investigated

Zhao et al. (2007)

Use of ionic liquids to improve the HPLC chromatographic the behavior of the analytes

Cruz-Vera et al. (2008)

Suárez et al. (2007a) Niu et al. (2007)

(Continued)

86  Chapter 2 Table 2.3: Applications of CNTs as SPE sorbents for the extraction of drugs. (cont.) Detection Techniques

CNTs Characteristics

Remarks

References

Serum and urine; pharmaceutical and foodstuffs Tap, river, and mineral water; honey Milk

Spectrofluorimetry

MWCNTs

—

Daneshvar Tarigh and Shemirani (2014)

MEKC

MWCNTs

—

Guan et al. (2010)

HPLC

MWCNTs

—

Bovine calf serum Human urine Serum

HPLC

MWCNTs

—

HPLC

MWCNTs

—

HPLC

MWCNTs

—

Spectrofluorimetry HPLC

MWCNTs

—

Doxorubicin

Human urine Rat tissues

—

Methylprednisolone

Rat plasma

HPLC

PEGylatede MWCNTs MWCNTs

Puerarin

Rat plasma

HPLC

PEGylatede MWCNTs

—

Ding et al. (2011) Zhang et al. (2011) Xiao et al. (2014) Xiao et al. (2013) Madrakian et al. (2013) Shen et al. (2011) Yu et al. (2014a) Yu et al. (2014b)

Analyte

Matrix

Thiamine

Diethylstilbestrol estrone estriol

Estradiol ethinyloestradiol hexestrol Bovine serum albumin Quercetin luteolin kaempferol Gatifloxacin Naproxen

—

sample preparation time, reduced the number of matrix manipulations and the samplepreparation steps, and avoided the introduction of sources of uncertainty in the analytical process. M-SPE involves the accumulation of magnetic sorbent particles to the sample solution. The external magnetic field is applied for the separation of sample when the target compound is adsorbed onto the magnetic material and the magnetic particle (containing the analyte). Finally, the analyte is recovered from the adsorbent by elution with the suitable solvent and it is subsequently analyzed. A general scheme for the M-SPE procedure is shown in Fig. 2.5. This access has a number of advantages over long-established SPE (Herrero-Latorre et al., 2015): 1. It averts time-consuming and tedious on-column SPE procedures. 2. It provides a rapid and simple analyte separation that avoids the need for centrifugation or filtration steps. 3. The magnetic sorbents have high selectivity, even when complex matrices from environmental or biological fields were analyzed.

Modern Extraction Techniques for Drugs and Medicinal Agents   87

Figure 2.5: The Procedure Used for Magnetic Solid-Phase Extraction (M-SPE) (Płotka-Wasylka et al., 2015).

4. Sample impurities are diamagnetic; they do not get in the way with magnetic particles during the magnetic separation step. 5. Automation of the whole process is possible with flow injection analysis and other related techniques, which leads to rapid, selective, sensitive, and repeatable methods for routine determinations. MSPE has been extensively used in many fields, including (Chen et al., 2012): 1. biomedicine, to separate cells and to isolate enzymes, proteins; 2. environmental science, for the isolation of pesticides, metal ions, dyes, PAHs, drugs, antibiotics, and carcinogenic, surfactants, and mutagenic compounds in water and sewage samples; 3. food analysis, to extract pesticides, antibiotics, metals, and drugs from different kinds of food samples.

2.8  Molecularly Imprinted Solid Phase Extraction (MISPE) Molecular imprinting is a method used for producing synthetic polymers with predetermined molecular recognition properties. Molecularly imprinting technology depends on the arrangement of a complex between an analyte (template) and a functional monomer. A huge surplus of a cross-linking agent is required to form a three-dimensional polymer network.

88  Chapter 2 After the polymerization process, the template is removed from the polymer leaving specific recognition sites complementary in shape, size, and chemical functionality to the template molecule. Mainly between the template molecules, intermolecular interaction, such as dipole– dipole, hydrogen bonds, and ionic interactions occurred. These interactions act as functional groups present in the polymer matrix and drive the molecular appreciation phenomena. Thus, the resultant polymer perceives and binds selectively only to the template molecules (Vasapollo et al., 2011). The principle of MISPE is based on the same main steps as conventional SPE: habituation of the sorbent, loading the sample, washing away interferences, and elution of the target analytes. In the second step, the sample is percolated through the molecularly imprinted polymer. It is significant to provide similar solvent polarity to that used in the polymerization process since it enhances the number of relations between the analyte and specific binding sites in the MIP sorbents. Acrylate-based MIPs became a popular choice as selective/specific sorbents for SPE and nowadays, applications of these conventional MIPs are focused on the large and complex molecules (Płotka-Wasylka et al., 2016). Recently, MIPs attracted much attention due to their outstanding advantages (He et al., 2007): 1. 2. 3. 4. 5.

predetermined recognition ability; mechanical and chemical stability; relative ease and simplicity of preparation; low cost of preparation; potential application to a wide range of target molecules.

Recently, MIPs have been attracting widespread interest in many fields of science, especially to mimic natural recognition entities, such as antibodies and biological receptors; they are also useful to separate and analyze complex materials, such as biological fluids, food, drug, and environmental samples (Płotka-Wasylka et al., 2016).

2.9  Solid-Phase Microextraction SPME is a class of SPE, in which SPME disposes of two of the largest substantial faults of SPE (i.e., the length of time for extraction and, more importantly, the need to use organic solvents). Sample preparation using SPME gained appreciation among a large group of analytical scientists because of the following benefits (Duan et al., 2011; Souza Silva et al., 2013; Spietelun et al., 2013). 1. The possibility of simultaneous download, concentration, and analyte determination, which significantly shortened the time to make an analysis. 2. High sensitivity (possibly to determine the substance at the ppt level). 3. Small sample size.

Modern Extraction Techniques for Drugs and Medicinal Agents   89 4. Simplicity and speed of analysis, where use of complicated equipment, tools, and devices or precise operations was not required. 5. Cost minimization by eliminating organic solvents and expensive toxic and multiple uses of SPME fibers. 6. Small fibers, which consent to the device to download samples in in situ conditions. 7. The prospect of automation. 8. The possibility of joining with other instrumental techniques—most often with liquid chromatography (LC), gas chromatography (GC), high-performance liquid chromatography (HPLC), and capillary electrophoresis (CE) in the off-line or on-line modes. The numerous advantages of SPME mean that it is almost universal, because it allows analysis of many kinds of the sample in different physical states—liquid, gas, and solid— often with very complex matrixes, and it contributes determination of analytes at trace and ultratrace levels. In SPME, thin fibers containing melted silica, coated with an appropriate sorption material, are engaged in catching the target analytes. Compounds that exist in the sample are divided into the matrix and the coated fiber. The quantity of absorbed analyte depends on the partition coefficients between the sorbent layer coating the fiber and the matrix of the samples and on the analyte affinity, the time of contact, and other variables (Lord and Pawliszyn, 2000).

2.10  Stir-Bar Sorptive Extraction Stir-bar sorptive extraction (SBSE) emerged as a novel application involving the use of polydimethylsiloxane (PDMS) polymer as a sorbent for SPE. SBSE is depended on the similar principles as SPME, but, as a substitute of a polymer-coated fiber, stir bars are coated with PDMS, and a polar polymeric phase is used for hydrophobic relations with target molecules (commercially available as Twister, Gerstel GmbH), whereas, the retention process in the PDMS phase is based on van der Waals forces and the hydrogen bonds that may be produced with oxygen atoms of PDMS, depending on the molecular structure of the target analytes. Due to its elimination of solvents and reduction of the labor-intensive and timeconsuming sample preparation step, SBSE also fulfills the requirements of green analytical chemistry (Nogueira, 2012). Sampling is done by introducing the SBSE device into the aqueous sample. While it is stirred, the bar absorbs analytes to be extracted. The bar is removed from the sample, rinsed with deionized water, and dried. Afterward, the analytes are desorbed from the enriched sorbent phase by thermal desorption (TD) but, in the case of analytes that decompose at low temperatures, the analytes are desorbed by liquid desorption (LD). The greatest applicable improvement to expand the significant SBSE would be new coatings, which would allow the analysis of polar compounds. Unfortunately, these compounds

90  Chapter 2 generally cannot be analyzed using gas chromatography (GC), and TD cannot be used. These new coating materials include (Płotka-Wasylka et al., 2015): 1. Polyurethane foams 2. Silicone materials 3. Poly (ethylene glycol)-modified silicone (EG Silicone Twister) 4. Poly(dimethylsiloxane)/polypyrrole 5. Polyvinyl alcohol 6. Poly(phthalazine ether sulfone ketone) 7. Polyacrylate (acrylate twister) 8. Carbon nanotube-polydimethylsiloxane) (CNT-PDMS) 9. Alkyl-diol-silica (ADS) constrained right of entry materials 10. Cyclodextrin 11. Monolithic materials 12. Sorbents obtained with sol–gel techniques The SBSE technique offers several advantages; however, since a single polar polymer covers the stir bar, it may only be applied to semivolatile, thermo-stable compounds. Moreover, SBSE has fewer disadvantages, such as (1) limited spectrum of analyte polarities for the offered stationary phases, (2) the existence of strong matrix effects, and (3) the need for high control of extraction conditions. SBSE is effectively applied to many analytical fields (e.g., clinical, environmental, and food analysis) and to different kinds of the matrix, including environmental water, wastewater, soils, biological fluids, and gaseous samples. SBSE-based methods have developed in the field of clinical analysis and pharmaceuticals (Table 2.4). However, the number of applications within this field is lower than in the field of environment and food analysis (Popp et al., 2001).

2.11  Electrical-Field-Induced Solid-Phase Extraction The electrical-field-induced solid-phase extraction (EF-SPE) technique is a topic that is less interrogate. Electrically or electrochemically induced solid-phase extraction techniques have originated significant applications in SPE and SPME techniques with the synthesis of sorbents and augmentation of extraction. Generally, an electrical field has two effects in the solid-based extraction techniques; it directly affects the surface of solid sorbents and provides manipulation possibility of extraction, or it has an indirect effect that only provides an electrokinetic migration of charged analytes toward solid sorbent or facilitates elution of the analytes (Yamini et al. 2014). The substantial escalating movement in application of the electrical field in solid depends on extraction techniques, which may be recognized for several reasons: 1. Properties of the conducting polymer can be modified by varying the conditions during the electropolymerization step to enable extraction of analytes with different sizes and charges.

Modern Extraction Techniques for Drugs and Medicinal Agents   91 Table 2.4: Applications of SBSE method for the extraction of drugs. Analyte

Matrix

Detection Techniques

SBSE-Coating Materials

Benzothiazole

Wastewater

GC–MS

PA

Ractopamine, isoxsuprine, clenbuterol, and fenoterol Ractopamine Ketamine Paracetamol, caffeine, antipyrine, propranolol, carbamazepine, ibuprofen, diclofenac, methylparaben, ethylparaben, and propylparaben Paracetamol, caffeine, antipyrine, propranolol, carbamazepine, naproxen, and diclofenac

Pork, liver, and feed Pork meat Urine River water, effluent and influent wastewater

HPLC-UV HPLC-FID ECL HPLC-UV LC–MS/MS

MIP with ractopamine MIP Titania-OH-TSO Hydrophilic polymer based on poly(N-vinylpyrrolidone-co-divinyl benzene)

Environmental water

LC–MS/MS

Poly(MAA-co-DVB)

References Camino-Sánchez et al. (2014) Xu et al. (2010a) Wang et al. (2012) Xu et al. (2010b) Bratkowska et al. (2011)

Bratkowska et al. (2012)

2. Compared to conventional solid-based extraction techniques, in which a material with a fixed number of exchange sites is employed, the electrically assisted technique offers higher flexibility. This is because the properties of the material and number of exchange sites may be on the outside prohibited by electrochemically controlling the charge of the material. 3. The use of polymer on the fiber films in solid-based extraction techniques may be comprehensive to the analysis of neutral, electro-inactive analytes by engaging the advantage of electrochemically controlled hydrophilic or hydrophobic “switching”. 4. Electrically assisted solid-based extraction techniques may be used for extractions and analytes that usually need to be derivatized prior to traditional solid-based extractions. 5. In electrically assisted solid based extraction techniques, the extraction and desorption steps are performed merely by changing the potential of the conducting polymercoated electrode. In this way, there is no need for changes of the solvent to for facilitate desorption of the compounds. 6. By altering the electrochemical potential of the polymer, desorption of electrostatically held analytes may also be faster compared to the desorption techniques normally used in traditional solid-based extractions. This makes the technique mainly attractive for utilizing in conjunction with miniaturized analytical systems.

2.12  Ultrasound-Assisted Extraction Ultrasound-assisted extraction (UAE) is regularly fetching a matter of routine practice in analytical chemistry, which uses this energy for a multiplicity of purposes in relation to

92  Chapter 2 sample preparation, mostly sample extraction. Solvent extraction of organic compounds enclosed within the seeds and plants are extensively enhanced by using the power of ultrasound. The mechanical property of ultrasound affords a greater solvent penetration into cellular materials and progress mass transfer due to the property of microstreaming. This is combined with an additional benefit of using ultrasound in extractive processes—namely, disruption of biological cell walls to release the cell contents. Overall, UAE is renowned as a competent extraction technique that dramatically reduces working times, increasing yields, and repeating the quality of the extract (Awad et al., 2012). Ultrasound consists of mechanical waves that require an elastic medium to spread. The difference between ultrasound and sound is the frequency of the wave; sound waves are at human-hearing frequencies (16 Hz to 16–20 kHz), whereas ultrasound has frequencies above human hearing but below microwave frequencies (from 20 kHz to 10 MHz). For the classification of ultrasound applications, the amount of energy generated, characterized by sound power (W), sound intensity (W/m2), or sound energy density (W/m3) is the key criterion. The uses of ultrasound is broadly distinguished into two groups: high intensity and low intensity (Chemat et al., 2011). Low-intensity ultrasound—high frequency (100 kHz–1 MHz), low power (typically